IndraLab
Statements
reach
"In fact, it was subsequently found that USP28 binds to MYC at the same motif recognized by Fbw7, but only when it is unphosphorylated, and promotes deubiquitination of MYC in the absence of Fbw7.104 Moreover, it has been reported that USP28 dissociates from Fbw7α in response to DNA damage, allowing MYC to be degraded by Fbw7α.105 Adding another layer of complexity in regulating MYC, USP28 was reported to control the stability of Fbw7 by antagonizing its auto-ubiquitination and degradation in specific tissues such as lung, pancreas and liver, leading to destabilization of Fbw7 targets and to dose-dependent effects in Usp28 knockout mice."
reach
"Interestingly, Yang et al. [75] identified a circular RNA encoding circ-FBXW7, whose expression in GBM samples was lower compared to the surrounding normal tissue, being capable of antagonizing the stabilization of the oncoprotein c-MYC initiated by the deubiquitinase USP28; circ-FBXW7 expression was linked to greater survival in patients."
sparser
"Several mechanisms of intrinsic resistance have been described among whom loss of PTEN, cyclin D1 amplification, loss of NF1, RAC1 P29S mutation, HGF secretion, MAP3K8 overexpression, loss of the USP28–FBW7 complex, low levels of CD8 tumor-infiltrating T cells and increased expression of the immune inhibitory molecule PD-L1 ( xref – xref )."
reach
"For instance, USP7 can promote cancer development by downregulating p53 levels through deubiquitination of mouse double minute 2 (MDM2); lysine 63 deubiquitinase (CYLD), which is frequently mutated in nasopharyngeal carcinoma, inhibits cell invasion and metastasis by interfering with the NF-κB signaling pathway; USP28 is an oncogenic factor that deubiquitinates F-box and WD repeat domain containing 7 (FBXW7), thereby enhancing the stability of RAF family members and inhibiting activation of the MEEK pathway."
reach
"Other proteins regulating C-MYC stability include : CIP2A, a C-MYC-interacting protein that specifically inhibits PP2A activity against C-MYC; USP28, a de-ubiquitinating enzymes that antagonizes FBW7 and promotes C-MYC stability and TRUSS, a receptor for DDB1 (damage specific DNA binding protein 1)-CUL4 (Cullin 4) E3 ligase complex."
reach
"A study has proposed a novel mechanism by which USP28 upregulates angiogenesis by antagonizing GSK-3beta (glycogen synthase kinase-3beta) and FBW7 dependent degradation of HIF-1alpha (hypoxia inducible factor-1alpha), a major regulator of angiogenesis, carcinogenesis, and various processes by which cells adapt to hypoxic conditions."
reach
"In fact, it was subsequently found that USP28 binds to MYC at the same motif recognized by Fbw7, but only when it is unphosphorylated, and promotes deubiquitination of MYC in the absence of Fbw7.104 Moreover, it has been reported that USP28 dissociates from Fbw7α in response to DNA damage, allowing MYC to be degraded by Fbw7α.105 Adding another layer of complexity in regulating MYC, USP28 was reported to control the stability of Fbw7 by antagonizing its auto-ubiquitination and degradation in specific tissues such as lung, pancreas and liver, leading to destabilization of Fbw7 targets and to dose-dependent effects in Usp28 knockout mice."
USP28 is modified
2
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2
82
USP28 is phosphorylated.
2
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42
sparser
"The USP25 activity may not be affected upon exposure to an inhibitor blocking the phosphorylation of USP28 on serine 67 and serine It could be another therapeutic option to target the binding between ATM and USP28 and reduce the phosphorylation of USP28, thus decreasing its enzymatic activity in cancer cells with increased DNA damage levels."
| PMC
USP28 is sumoylated.
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22
USP28 is desumoylated.
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13
USP28 is methylated.
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1
4
USP28 is ubiquitinated.
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1
USP28 is produced.
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1
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"Moreover, upregulated TET1 directly demethylates USP28 promoter, thereby enhancing USP28 transcription and expression, which binds to CD44s protein, and remove the ubiquitin group from the ubiquitinated CD44s protein, resulting in stabilization of CD44s protein to mediate stem like property of human BC cells."
reach
"Understanding how 53BP1 and USP28 elevate p53 in response to centrosome loss and extended mitotic duration, and determining whether centrosome loss is an independent input into the p53 circuit or triggers p53 elevation because it leads to sequential prolonged mitoses, are important future goals arising from the results described here."
sparser
"This hypothesis is further supported by biochemical work showing that both p53 and USP28 interact with the tandem-BRCT domains of 53BP1 [ xref – xref ], which are dispensable for the DNA damage response role of 53BP1 [ xref ], but are required for the centrosome surveillance pathway [ xref ]."
sparser
"Strikingly, unlike unstressedp21 -/- cells that mostly lacked nuclear p53, in the stressed condition, p53 not only was stabilized in the nucleus, but also formed bright nuclear foci of various sizes co-localizing with 53BP1 and USP28 in ~30% of the cell population ( xref ), suggesting that 53BP1, USP28 and p53 interact with each other after a stressed mitosis, consistent with the known interaction between 53BP1 and p53 or USP28 ( xref ; xref ; xref )."
sparser
"While much remains to be learned about how the mitotic surveillance pathway functions to survey centrosomes, a plausible model is that in response to centrosome loss, 53BP1 binds to USP28 and p53 to facilitate USP28-dependent deubiquitination and activation of p53, leading to cell cycle arrest xref , xref ( xref )."
sparser
"Strikingly, unlike unstressedp21 -/- cells that mostly lacked nuclear p53, in the stressed condition, p53 not only was stabilized in the nucleus, but also formed bright nuclear foci of various sizes co-localizing with 53BP1 and USP28 in ~30% of the cell population ( xref ), suggesting that 53BP1, USP28 and p53 interact with each other after a stressed mitosis, consistent with the known interaction between 53BP1 and p53 or USP28 ( xref ; xref ; xref )."
sparser
"While much remains to be learned about how the mitotic surveillance pathway functions to survey centrosomes, a plausible model is that in response to centrosome loss, 53BP1 binds to USP28 and p53 to facilitate USP28-dependent deubiquitination and activation of p53, leading to cell cycle arrest xref , xref ( xref )."
reach
"USP28 also modulates the DNA damage response (DDR) in cancer cells by deubiquitinating and stabilising the checkpoint kinase 2 (CHK2), the TP53-binding protein 1 (TP53BP1) and Claspin (CLSPN) [6, 7], thereby preventing apoptosis but establishing cell cycle arrest to facilitate DNA repair [8]."
sparser
"Strikingly, unlike unstressedp21 -/- cells that mostly lacked nuclear p53, in the stressed condition, p53 not only was stabilized in the nucleus, but also formed bright nuclear foci of various sizes co-localizing with 53BP1 and USP28 in ~30% of the cell population ( xref ), suggesting that 53BP1, USP28 and p53 interact with each other after a stressed mitosis, consistent with the known interaction between 53BP1 and p53 or USP28 ( xref ; xref ; xref )."
sparser
"While much remains to be learned about how the mitotic surveillance pathway functions to survey centrosomes, a plausible model is that in response to centrosome loss, 53BP1 binds to USP28 and p53 to facilitate USP28-dependent deubiquitination and activation of p53, leading to cell cycle arrest xref , xref ( xref )."
USP28 affects cell population proliferation
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USP28 activates cell population proliferation.
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USP28 activates cell population proliferation. 10 / 43
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USP28 bound to FBXW7 activates cell population proliferation. 1 / 1
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USP28 inhibits cell population proliferation.
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USP28 inhibits cell population proliferation. 10 / 16
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16
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"LncRNA-SNHG14/miRNA-3940-5p/NAP12 mRNA may be potential for CRC diagnosis and prognosis.8 miR-3940-5p negatively regulates CUL7 and activates NF-κB to promote gliomagenesis in human gliomas.38 miR-3940-5p targets CCND1 and USP28 to inhibit proliferation and induce apoptosis in NSCLC cells."
sparser
"Several mechanisms of intrinsic resistance have been described among whom loss of PTEN, cyclin D1 amplification, loss of NF1, RAC1 P29S mutation, HGF secretion, MAP3K8 overexpression, loss of the USP28–FBW7 complex, low levels of CD8 tumor-infiltrating T cells and increased expression of the immune inhibitory molecule PD-L1 ( xref – xref )."
sparser
"A previous study demonstrated that the deubiquitinating enzyme USP28 directly interacts with STAT3 and increases its stability. xref Thus, regulation of STAT3 acetylation and recruitment of E3 ligase or deubiquitinating enzymes might be associated with the regulation of STAT3 protein stability by SA14."
reach
"To examine whether interaction of HDAC5 with LSD1 and USP28 complex deacetylates LSD1 or USP28, in vitro protein acetylation assays was first carried out by incubating GST tagged recombinant HDAC5 protein with cellular pull-down of LSD1-FLAG or USP28-FLAG by IP, and immunoprecipitates of IgG was incubated with recombinant HDAC5 protein as negative control of assays (XREF_FIG)."
sparser
"Additionally, the level and activity of the histone demethylase lysine specific demethylase 1 (LSD1) can be controlled by USP28 through a deubiquitination event, during which an amine oxidase domain in LSD1 and the N-terminal region of USP28 are responsible for the LSD1 interaction with USP28 [ xref ]."
reach
"The results above suggest that USP28 may stimulate EMT via its deubiquitination of LSD1 and Snail and then suppress EMT-related molecules.In addition to the molecules involved in EMT, other molecules, such as Lin28A, which is a crucial regulator of invasiveness, can also accelerate metastasis [84]."
reach
"Therefore, USP28 can maintain Notch signaling, through which cell differentiation is inhibited.Moreover, LSD1, which can be deubiquitinated by USP28, has the capacity to regulate pluripotency markers such as octamer-binding transcription factor 4 (Oct4) and SRY-related HMG box-containing 2 (SOX2) and the differentiation gene p21 [9, 83, 91]."
reach
"To understand whether HDAC5 may stabilize LSD1 protein through upregulation of USP28 protein stability, a rescue study was carried out in MDA-MB-231 and MCF10A-CA1a cells using concurrent transfection of HDAC5 siRNA and USP28 expression plasmids, and showed that overexpression of USP28 completely blocked the destabilization of LSD1 by HDAC5 depletion (XREF_FIG, XREF_SUPPLEMENTARY)."
sparser
"This hypothesis is further supported by biochemical work showing that both p53 and USP28 interact with the tandem-BRCT domains of 53BP1 [ xref – xref ], which are dispensable for the DNA damage response role of 53BP1 [ xref ], but are required for the centrosome surveillance pathway [ xref ]."
sparser
"Strikingly, unlike unstressedp21 -/- cells that mostly lacked nuclear p53, in the stressed condition, p53 not only was stabilized in the nucleus, but also formed bright nuclear foci of various sizes co-localizing with 53BP1 and USP28 in ~30% of the cell population ( xref ), suggesting that 53BP1, USP28 and p53 interact with each other after a stressed mitosis, consistent with the known interaction between 53BP1 and p53 or USP28 ( xref ; xref ; xref )."
sparser
"While much remains to be learned about how the mitotic surveillance pathway functions to survey centrosomes, a plausible model is that in response to centrosome loss, 53BP1 binds to USP28 and p53 to facilitate USP28-dependent deubiquitination and activation of p53, leading to cell cycle arrest xref , xref ( xref )."
reach
"The findings that support this conclusion are the following : (i) the binding of UCK1 to the E3 ligase KLHL2 causes its polyubiquitination at K81 and degradation; (ii) the DUB USP28 binds to UCK1 through interaction with KLHL2 and antagonizes KLHL2 mediated effect on UCK1; (iii) UCK1 deubiquitination by USP28 is dependent on the phosphorylation status of USP28; (iv) USP28 is phosphorylated by 5 '-AZA-activated ATM, resulting in disassociation of KLHL2 from USP28 and UCK1 destabilization; (v) ATM also phosphorylates UCK1 at S145, significantly enhancing the KLHL2 and UCK1 complex formation; (vi) the knockdown of KLHL2 not only significantly inhibits AML cell proliferation, but also sensitizes AML cells to 5 '-AZA-induced apoptosis; and (vii) combinational therapies with 5 '-AZA and ectopic USP28 expression enhances the effects of 5 '-AZA and induces synergistic lethality at cellular level and in the AML mouse model, which is, however, observed in cells deficient in USP28."
sparser
"The findings that support this conclusion are the following: (i) the binding of UCK1 to the E3 ligase KLHL2 causes its polyubiquitination at K81 and degradation; (ii) the DUB USP28 binds to UCK1 through interaction with KLHL2 and antagonizes KLHL2-mediated effect on UCK1; (iii) UCK1 deubiquitination by USP28 is dependent on the phosphorylation status of USP28; (iv) USP28 is phosphorylated by 5'-AZA-activated ATM, resulting in disassociation of KLHL2 from USP28 and UCK1 destabilization; (v) ATM also phosphorylates UCK1 at S145, significantly enhancing the KLHL2-UCK1 complex formation; (vi) the knockdown of KLHL2 not only significantly inhibits AML cell proliferation, but also sensitizes AML cells to 5'-AZA-induced apoptosis; and (vii) combinational therapies with 5'-AZA and ectopic USP28 expression enhances the effects of 5'-AZA and induces synergistic lethality at cellular level and in the AML mouse model, which is, however, observed in cells deficient in USP28."
UCK1 binds USP28 and Hemagglutinins. 1 / 1
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1
reach
"To examine whether interaction of HDAC5 with LSD1 and USP28 complex deacetylates LSD1 or USP28, in vitro protein acetylation assays was first carried out by incubating GST tagged recombinant HDAC5 protein with cellular pull-down of LSD1-FLAG or USP28-FLAG by IP, and immunoprecipitates of IgG was incubated with recombinant HDAC5 protein as negative control of assays (XREF_FIG)."
sparser
"Additionally, the level and activity of the histone demethylase lysine specific demethylase 1 (LSD1) can be controlled by USP28 through a deubiquitination event, during which an amine oxidase domain in LSD1 and the N-terminal region of USP28 are responsible for the LSD1 interaction with USP28 [ xref ]."
sparser
"Once all the three conservative SQ sites (S67, S495, and S714), in USP28, were mutated to alanine, the pS/TQ antibody completely could not recognize the immunoprecipitated Flag-USP28-3S/A (Figure xref D), suggesting that in response to 5'-AZA-induced stress, ATM phosphorylates USP28 at all these three sites."
reach
"Once all the three conservative SQ sites (S67, S495, and S714), in USP28, were mutated to alanine, the pS/TQ antibody completely could not recognize the immunoprecipitated Flag-USP28-3S/A, suggesting that in response to 5 '-AZA-induced stress, ATM phosphorylates USP28 at all these three sites."
reach
"The USP25 activity may not be affected upon exposure to an inhibitor blocking the phosphorylation of USP28 on serine 67 and serine It could be another therapeutic option to target the binding between ATM and USP28 and reduce the phosphorylation of USP28, thus decreasing its enzymatic activity in cancer cells with increased DNA damage levels."
| PMC
reach
"Likewise, Annexin-V-positive cells were increased in USP28-KO clones compared with USP28-depleted cells reconstituted with USP28 or MAST1 (Fig. 5G), indicating that loss of USP28 sensitizes cells to cisplatin-mediated DNA damage and induced cell death.Finally, we wished to investigate the molecular mechanism of USP28 regulation on MAST1-driven cisplatin-resistance."
reach
"An anchorage-independent colony formation assay demonstrated that USP28-KO clones showed reduced colony numbers compared with the mock control, while the colony-forming ability was increased in USP28-depleted cells reconstituted with USP28 or MAST1 (Fig. 6A and Supplementary Fig. 15A)."
reach
"Furthermore, we showed that the loss of USP28 downregulates MAST1 protein level and sensitizes cells for cisplatin toxicity during tumor growth, leading to reduced tumor size, volume and weight.In conclusion, our study demonstrates that USP28 could enhance MAST1-driven cisplatin resistance by stabilizing MAST1 protein level in cancer."
sparser
"A previous study demonstrated that the deubiquitinating enzyme USP28 directly interacts with STAT3 and increases its stability. xref Thus, regulation of STAT3 acetylation and recruitment of E3 ligase or deubiquitinating enzymes might be associated with the regulation of STAT3 protein stability by SA14."
reach
"The identification of several DUB inhibitors, including inhibitors of USP28, which regulate various oncogenes (e.g., c-Myc) and USP25, which regulates TRAF (tumor necrosis factor receptor-associated factor) signalling, provide alternative approaches to induce degradation of potential “un-druggable” molecules in cancer.Gerry Melino (University of Cambridge, UK) presented data demonstrating the p53 family protein TAp73, facilitates ubiquitin-dependent degradation of HIF1α, thereby suppressing tumor progression."
USP28 affects apoptotic process
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19
USP28 activates apoptotic process.
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USP28 activates apoptotic process. 10 / 11
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reach
"LncRNA-SNHG14/miRNA-3940-5p/NAP12 mRNA may be potential for CRC diagnosis and prognosis.8 miR-3940-5p negatively regulates CUL7 and activates NF-κB to promote gliomagenesis in human gliomas.38 miR-3940-5p targets CCND1 and USP28 to inhibit proliferation and induce apoptosis in NSCLC cells."
USP28 inhibits apoptotic process.
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8
reach
"USP28 also modulates the DNA damage response (DDR) in cancer cells by deubiquitinating and stabilising the checkpoint kinase 2 (CHK2), the TP53-binding protein 1 (TP53BP1) and Claspin (CLSPN) [6, 7], thereby preventing apoptosis but establishing cell cycle arrest to facilitate DNA repair [8]."
sparser
"However, the half-life of MAST1 protein was rescued when USP28-KO cells were reconstituted with Flag-USP28 (Fig. xref J, lane 9–12; Supplementary Fig. 4A, lane 9–12), while USP28CA failed to increase the half-life of MAST1 protein (Fig. xref K, lane 9–12; Supplementary Fig. 4B, lane 9–12)."
reach
"The findings that support this conclusion are the following : (i) the binding of UCK1 to the E3 ligase KLHL2 causes its polyubiquitination at K81 and degradation; (ii) the DUB USP28 binds to UCK1 through interaction with KLHL2 and antagonizes KLHL2 mediated effect on UCK1; (iii) UCK1 deubiquitination by USP28 is dependent on the phosphorylation status of USP28; (iv) USP28 is phosphorylated by 5 '-AZA-activated ATM, resulting in disassociation of KLHL2 from USP28 and UCK1 destabilization; (v) ATM also phosphorylates UCK1 at S145, significantly enhancing the KLHL2 and UCK1 complex formation; (vi) the knockdown of KLHL2 not only significantly inhibits AML cell proliferation, but also sensitizes AML cells to 5 '-AZA-induced apoptosis; and (vii) combinational therapies with 5 '-AZA and ectopic USP28 expression enhances the effects of 5 '-AZA and induces synergistic lethality at cellular level and in the AML mouse model, which is, however, observed in cells deficient in USP28."
sparser
"The findings that support this conclusion are the following: (i) the binding of UCK1 to the E3 ligase KLHL2 causes its polyubiquitination at K81 and degradation; (ii) the DUB USP28 binds to UCK1 through interaction with KLHL2 and antagonizes KLHL2-mediated effect on UCK1; (iii) UCK1 deubiquitination by USP28 is dependent on the phosphorylation status of USP28; (iv) USP28 is phosphorylated by 5'-AZA-activated ATM, resulting in disassociation of KLHL2 from USP28 and UCK1 destabilization; (v) ATM also phosphorylates UCK1 at S145, significantly enhancing the KLHL2-UCK1 complex formation; (vi) the knockdown of KLHL2 not only significantly inhibits AML cell proliferation, but also sensitizes AML cells to 5'-AZA-induced apoptosis; and (vii) combinational therapies with 5'-AZA and ectopic USP28 expression enhances the effects of 5'-AZA and induces synergistic lethality at cellular level and in the AML mouse model, which is, however, observed in cells deficient in USP28."
UCK1 binds USP28 and Hemagglutinins. 1 / 1
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sparser
"However, the half-life of MAST1 protein was rescued when USP28-KO cells were reconstituted with Flag-USP28 (Fig. xref J, lane 9–12; Supplementary Fig. 4A, lane 9–12), while USP28CA failed to increase the half-life of MAST1 protein (Fig. xref K, lane 9–12; Supplementary Fig. 4B, lane 9–12)."
reach
"The results above suggest that USP28 may stimulate EMT via its deubiquitination of LSD1 and Snail and then suppress EMT-related molecules.In addition to the molecules involved in EMT, other molecules, such as Lin28A, which is a crucial regulator of invasiveness, can also accelerate metastasis [84]."
USP28 affects cell growth
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1
USP28 activates cell growth.
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8
USP28 inhibits cell growth.
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USP28 affects cell cycle
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USP28 activates cell cycle.
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USP28 activates cell cycle. 10 / 11
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"Similarly, western blot analyses revealed that the total p53 levels in 53BP1 -/- or USP28 -/- cells were kept low during acentrosomal cell division in the presence of mitotic delay (XREF_FIG), indicating that 53BP1 and USP28 function upstream of p53 to initiate cell cycle arrest in response to centrosome loss."
USP28 inhibits cell cycle.
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3
MiR-3940-5p affects USP28
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MiR-3940-5p inhibits USP28.
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MiR-3940-5p activates USP28.
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5
MiR-3940-5p decreases the amount of USP28.
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2
USP28 activates USP28.
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4
reach
"However, a trend towards increased USP28 protein expression was detected in CD3/CD28 activated helper T cells at 72h compared to resting naïve T cells (
Figure 1C
), suggesting that USP28 protein levels are induced by T cell activation.To better understand the role of USP28 in T cells, USP28 knockout (USP28 ) and their littermate control mice (USP28 ) were generated as previously described (24)."
USP28 inhibits USP28.
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3
reach
"Similarly to the case of NRF2, the deubiquitinases can prevent the degradation of HIF-1α so their activity must be taken into consideration when developing a possible therapy based on the increased HIF-1α ubiquitination.For example, the ubiquitination of HIF-1α mediated by FBXW7, analyzed earlier in this review, may be inhibited by the action of the Ubiquitin Specific Peptidase 28 (USP28), which acts as a FBXW7 regulator [102]."
reach
"However, a trend towards increased USP28 protein expression was detected in CD3/CD28 activated helper T cells at 72h compared to resting naïve T cells (
Figure 1C
), suggesting that USP28 protein levels are induced by T cell activation.To better understand the role of USP28 in T cells, USP28 knockout (USP28 ) and their littermate control mice (USP28 ) were generated as previously described (24)."
USP28 deubiquitinates USP28.
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USP28 decreases the amount of USP28.
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USP28 sumoylates USP28.
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USP28 methylates USP28.
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reach
"USP28 also modulates the DNA damage response (DDR) in cancer cells by deubiquitinating and stabilising the checkpoint kinase 2 (CHK2), the TP53-binding protein 1 (TP53BP1) and Claspin (CLSPN) [6, 7], thereby preventing apoptosis but establishing cell cycle arrest to facilitate DNA repair [8]."
reach
"Importantly, of the 59 patients harboring BRAF V600E mutations 27% (16/59) displayed a> 50% decrease in USP28 mRNA expression levels, suggesting that in tumors harboring BRAF alterations, loss of USP28 may further increase the tumorigenic potential of these tumors by stabilizing BRAF and enhancing downstream MAPK activation."
Vismodegib affects USP28
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Vismodegib binds USP28.
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8
Vismodegib inhibits USP28.
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3
sparser
"Given TRIM21 is not feasible as a therapeutic target for cardiac hypertrophy, due to its widespread expression in multi-organs, the cardiomyocyte-specific USP28-TRIM21 axis may avoid the potential and systemic side-effects induced by targeting TRIM21 alone, suggesting that targeting USP28 is a more specific strategy for cardiac hypertrophy therapy."
reach
"Specifically, the present study assessed whether RSV would disrupt the interactions between Lin28A and USP28 or prevents ERK1/2-mediated phosphorylation at S200.The MTT assay results in the present study agreed with previous reports (31,32), indicating that RSV inhibited NCCIT cell viability in a dose-dependent manner with an IC of 148 µM. All experiments were performed using the same concentrations (25–150 µM)."
reach
"Given that the degradation of Lin28A was by the proteasomal pathway, this could explain the stability of Lin28A protein as USP28 deubiquitinase was also downregulated at high RSV concentrations, and at 72 and 96 h.
Inhibition of USP28 using siUSP28 decreases the levels of Lin28A, but the reduction is less pronounced compared to the decrease observed after RSV treatment."
sparser
"Consistent with our data, computational modeling of structures predicted by the ZDOCK and PyMol software showed that Ser145 is the critical amino acid mediating the direct binding of UCK1 to KLHL2 (Figure xref J) while Ser67 phosphorylation disrupts the interaction between USP28 and KLHL2 (Figure xref K)."
sparser
"The findings that support this conclusion are the following: (i) the binding of UCK1 to the E3 ligase KLHL2 causes its polyubiquitination at K81 and degradation; (ii) the DUB USP28 binds to UCK1 through interaction with KLHL2 and antagonizes KLHL2-mediated effect on UCK1; (iii) UCK1 deubiquitination by USP28 is dependent on the phosphorylation status of USP28; (iv) USP28 is phosphorylated by 5'-AZA-activated ATM, resulting in disassociation of KLHL2 from USP28 and UCK1 destabilization; (v) ATM also phosphorylates UCK1 at S145, significantly enhancing the KLHL2-UCK1 complex formation; (vi) the knockdown of KLHL2 not only significantly inhibits AML cell proliferation, but also sensitizes AML cells to 5'-AZA-induced apoptosis; and (vii) combinational therapies with 5'-AZA and ectopic USP28 expression enhances the effects of 5'-AZA and induces synergistic lethality at cellular level and in the AML mouse model, which is, however, observed in cells deficient in USP28."
reach
"A study has proposed a novel mechanism by which USP28 upregulates angiogenesis by antagonizing GSK-3beta (glycogen synthase kinase-3beta) and FBW7 dependent degradation of HIF-1alpha (hypoxia inducible factor-1alpha), a major regulator of angiogenesis, carcinogenesis, and various processes by which cells adapt to hypoxic conditions."
USP28 affects DNA Damage
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USP28 activates DNA Damage.
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USP28 activates DNA Damage. 7 / 7
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7
reach
"Arrest of cell cycle by serum deprivation also decreased and equalized γH2AX levels in both cell lines (Supplementary Figure S3C), suggesting that DNA damage induced by monomeric USP28 requires DNA replication.Assessment of DNA breakage using neutral comet assay (60) showed an increased level of DSBs in cells expressing USP28-M compared to USP28-WT (Figure 3D)."
reach
"Summarizing the research findings above, we can link USP28 inhibition and AZ1-induced events such as cell cycle alterations, apoptosis, immune activation, and DNA damage: Targeting USP28 induces DNA damage, activating Noxa-mediated mitochondrial apoptosis; DNA damage and mitochondrial apoptosis release dsDNA and mtDNA which activate tumor cell immunogenicity via the cGAS-STING signaling pathway; simultaneously targeting USP28 leads to c-MYC degradation, causing cell cycle arrest and inhibition of DNA repair, further promoting DNA damage-induced cell apoptosis mediated by Noxa protein, thereby enhancing tumor cell immunogenicity mediated by dsDNA and mtDNA.Platinum-based drugs are commonly used DNA-damaging agents widely employed in the treatment of malignant tumors."
USP28 inhibits DNA Damage.
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USP28 inhibits DNA Damage. 3 / 3
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3
reach
"Likewise, Annexin-V-positive cells were increased in USP28-KO clones compared with USP28-depleted cells reconstituted with USP28 or MAST1 (Fig. 5G), indicating that loss of USP28 sensitizes cells to cisplatin-mediated DNA damage and induced cell death.Finally, we wished to investigate the molecular mechanism of USP28 regulation on MAST1-driven cisplatin-resistance."
sparser
"Given TRIM21 is not feasible as a therapeutic target for cardiac hypertrophy, due to its widespread expression in multi-organs, the cardiomyocyte-specific USP28-TRIM21 axis may avoid the potential and systemic side-effects induced by targeting TRIM21 alone, suggesting that targeting USP28 is a more specific strategy for cardiac hypertrophy therapy."
reach
"AZ1, VSM, and FT206 bind to USP28 at different overlapping positions inside the same hydrophobic cleft, located at the intersection of the USP-thumb and palm subdomains in the center of the concave part of the USP S1-site, which acts as a binding surface for the globular domain of the distal Ub moiety of the cleaved substrate (Figs."
sparser
"Consistent with our data, computational modeling of structures predicted by the ZDOCK and PyMol software showed that Ser145 is the critical amino acid mediating the direct binding of UCK1 to KLHL2 (Figure xref J) while Ser67 phosphorylation disrupts the interaction between USP28 and KLHL2 (Figure xref K)."
sparser
"The findings that support this conclusion are the following: (i) the binding of UCK1 to the E3 ligase KLHL2 causes its polyubiquitination at K81 and degradation; (ii) the DUB USP28 binds to UCK1 through interaction with KLHL2 and antagonizes KLHL2-mediated effect on UCK1; (iii) UCK1 deubiquitination by USP28 is dependent on the phosphorylation status of USP28; (iv) USP28 is phosphorylated by 5'-AZA-activated ATM, resulting in disassociation of KLHL2 from USP28 and UCK1 destabilization; (v) ATM also phosphorylates UCK1 at S145, significantly enhancing the KLHL2-UCK1 complex formation; (vi) the knockdown of KLHL2 not only significantly inhibits AML cell proliferation, but also sensitizes AML cells to 5'-AZA-induced apoptosis; and (vii) combinational therapies with 5'-AZA and ectopic USP28 expression enhances the effects of 5'-AZA and induces synergistic lethality at cellular level and in the AML mouse model, which is, however, observed in cells deficient in USP28."
Otilonium bromide affects USP28
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9
Otilonium bromide binds USP28.
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6
Otilonium bromide inhibits USP28.
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3
USP28 affects vismodegib
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8
USP28 affects glycolytic process
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8
reach
"Importantly, of the 59 patients harboring BRAF V600E mutations 27% (16/59) displayed a> 50% decrease in USP28 mRNA expression levels, suggesting that in tumors harboring BRAF alterations, loss of USP28 may further increase the tumorigenic potential of these tumors by stabilizing BRAF and enhancing downstream MAPK activation."
reach
"Additionally, two other studies demonstrated that deubiquitylation and stabilization of FoxM1 by USP5 and USP28 contribute to its nuclear accumulation, which facilitates the recruitment of β-catenin to the Wnt target gene promoter and activates the Wnt signaling pathway (Chen et al., 2016; Chen L. et al., 2021)."
reach
"In another study, a reduction in G0/G1-phase cells and an increase in S-phase cells were observed in pancreatic cancer cells with ectopic expression of USP28, and this advancement in cell proliferation was mediated by the deubiquitination of Forkhead box M1 (FOXM1), which is induced by USP28 [4]."
sparser
"Strikingly, unlike unstressedp21 -/- cells that mostly lacked nuclear p53, in the stressed condition, p53 not only was stabilized in the nucleus, but also formed bright nuclear foci of various sizes co-localizing with 53BP1 and USP28 in ~30% of the cell population ( xref ), suggesting that 53BP1, USP28 and p53 interact with each other after a stressed mitosis, consistent with the known interaction between 53BP1 and p53 or USP28 ( xref ; xref ; xref )."
sparser
"While much remains to be learned about how the mitotic surveillance pathway functions to survey centrosomes, a plausible model is that in response to centrosome loss, 53BP1 binds to USP28 and p53 to facilitate USP28-dependent deubiquitination and activation of p53, leading to cell cycle arrest xref , xref ( xref )."
∆NP63 affects USP28
|
7
sparser
"To investigate a therapeutic potential of targeting the USP28‐∆Np63 axis in SCC cells of different origins, we used a set of human cancer cell lines, comprising the pancreas lines PANC‐1 (ADC) and BXPC‐3 (SCC); cervical cancer cell lines HeLa (ADC), SiHa and Ca Ski (SCC); the head‐and‐neck cell line Detroit 562 (SCC); and the lung cell lines H1299 (ADC) and LUDLU‐1 adh (SCC)."
USP28 affects ∆NP63
|
7
sparser
"To investigate a therapeutic potential of targeting the USP28‐∆Np63 axis in SCC cells of different origins, we used a set of human cancer cell lines, comprising the pancreas lines PANC‐1 (ADC) and BXPC‐3 (SCC); cervical cancer cell lines HeLa (ADC), SiHa and Ca Ski (SCC); the head‐and‐neck cell line Detroit 562 (SCC); and the lung cell lines H1299 (ADC) and LUDLU‐1 adh (SCC)."
USP28 affects miR-3940-5p
|
7
reach
"In combination with a significant negative correlation between expressions of miR-3940-5p versus CCND1 mRNA and USP28 mRNA in NSCLC tissues, these results suggest that CCND1 and USP28 are functional targets of miR-3940-5p and miR-3940-5p affects proliferation and apoptosis in A549 cells by targeting CCND1 and USP28."
USP28 affects cell differentiation
|
7
USP28 activates cell differentiation.
|
4
USP28 inhibits cell differentiation.
|
3
USP28 affects Neoplasm Metastasis
|
7
USP28 activates Neoplasm Metastasis.
|
6
USP28 inhibits Neoplasm Metastasis.
|
1
USP28 inhibits Neoplasm Metastasis. 1 / 1
|
1
USP28 affects otilonium bromide
|
6
USP28 affects cellular senescence
|
6
USP28 affects HM26
|
6
reach
"Moreover, upregulated TET1 directly demethylates USP28 promoter, thereby enhancing USP28 transcription and expression, which binds to CD44s protein, and remove the ubiquitin group from the ubiquitinated CD44s protein, resulting in stabilization of CD44s protein to mediate stem like property of human BC cells."
reach
"Collectively, our results strongly demonstrate that ATG7 overexpression mediated TET1 upregulation contributes to usp28 promoter demethylation, thereby increasing USP28 expression, consequently resulting in CD44s protein accumulation, and finally enhancing BC stem sphere formation, invasion, and lung metastatic activity."
reach
"Collectively, our results demonstrate that ATG7 autophagic removal of AUF1 promotes tet1 mRNA stabilization, which demethylates usp28 promoter, and in turn resulting in accumulation of CD44s protein, finally promoting cancer stem like properties, invasion and lung metastatic activity of human high invasive BC cells as shown in XREF_FIG."
reach
"Collectively, our results strongly demonstrate that ATG7 overexpression mediated TET1 upregulation contributes to usp28 promoter demethylation, thereby increasing USP28 expression, consequently resulting in CD44s protein accumulation, and finally enhancing BC stem sphere formation, invasion, and lung metastatic activity."
SGH affects USP28
|
1
5
SGH inhibits USP28.
|
1
3
reach
"In terms of mechanism of action, SGH downregulated cell cycle- and nucleotide synthesis related proteins to block cell cycle at G0/G1 phase, reduced the expression levels of glycolytic metabolic enzymes to inhibit glycolysis, and downregulated the important cancer transcription factor c-Myc and the therapeutic target deubiquitinase USP28."
SGH decreases the amount of USP28.
|
2
reach
"Specifically, the present study assessed whether RSV would disrupt the interactions between Lin28A and USP28 or prevents ERK1/2-mediated phosphorylation at S200.The MTT assay results in the present study agreed with previous reports (31,32), indicating that RSV inhibited NCCIT cell viability in a dose-dependent manner with an IC of 148 µM. All experiments were performed using the same concentrations (25–150 µM)."
HM26 affects USP28
|
6
reach
"Herein, we found that specific knockdown ATG7 resulted in usp28 promoter hypermethylation as comparison to scramble nonsense transfectants in human BC cells, and increased USP28 expression with 5-aza-2-deoxycytidine treatment, strongly indicating that the promoter hypermethylation was responsible for USP28 transcription downregulation due to ATG7 knockdown."
MiR-4295 affects USP28
|
5
USP28 affects angiogenesis
|
5
USP28 activates angiogenesis. 5 / 5
|
5
reach
"A study has proposed a novel mechanism by which USP28 upregulates angiogenesis by antagonizing GSK-3beta (glycogen synthase kinase-3beta) and FBW7 dependent degradation of HIF-1alpha (hypoxia inducible factor-1alpha), a major regulator of angiogenesis, carcinogenesis, and various processes by which cells adapt to hypoxic conditions."
USP28 affects Neoplasm Invasiveness
|
5
USP28 activates Neoplasm Invasiveness.
|
3
USP28 inhibits Neoplasm Invasiveness.
|
2
USP28 affects DNA replication
|
5
USP28 activates DNA replication.
|
3
USP28 inhibits DNA replication.
|
2
USP28 affects Carcinogenesis
|
2
3
sparser
"AZ1, VSM, and FT206 bind to USP28 at different overlapping positions inside the same hydrophobic cleft, located at the intersection of the USP-thumb and palm subdomains in the center of the concave part of the USP S1-site, which acts as a binding surface for the globular domain of the distal Ub moiety of the cleaved substrate (Figs. xref and xref )."
sparser
"However, the observation that the three structurally and chemically different compounds AZ1, VSM, and FT206 interact with USP28 in the same cleft, yet exert their inhibitory activity for USP28 and its close homolog USP25 without significantly affecting other DUBs of the USP family, prompted us to further investigate the origin of this selectivity."
Nickel(2+) affects USP28
|
4
MiR-500a-5p affects USP28
|
1
3
USP28 affects cell death
|
1
3
USP28 inhibits cell death.
|
1
1
USP28 activates cell death.
|
2
USP28 affects Wnt signaling pathway
|
3
1
USP28 activates Wnt signaling pathway. 4 / 4
|
3
1
eidos
"Our results show that USP28 contributes to the activity of the Wnt signaling pathway through stabilizing TCF7L2 ( Figure 7 ) , at least partially , as it also regulates other members of the TCF / LEF family transcription factors ( Figure 2A ) as well as Forkhead box protein M1 ( FOXM1 ) , another transcription factor involved in Wnt signaling ."
sparser
"RNA sequencing, immunoprecipitation and mass spectrometry analysis, chromatin immunoprecipitation assays, chromatin immunoprecipitation sequencing, and protein pull-down assay mechanistically revealed that USP28 directly interacted with PPARα (peroxisome proliferator-activated receptor α), deubiquitinating and stabilizing PPARα (Lys152) to promote Mfn2 (mitofusin 2) transcription, thereby impeding mitochondrial morphofunctional defects."
reach
"We found that depletion of USP28 reduces the expression of multiple MVP proteins, most prominently enzymes that catalyse the sequential condensation of acetoacetyl-CoA to form isoprenoid chains that are used for protein prenylation and for the synthesis important cellular metabolites, including CoQ10, dolichol and cholesterol."
USP28 affects FBXW7-185aa
|
4
sparser
"RNA sequencing, immunoprecipitation and mass spectrometry analysis, chromatin immunoprecipitation assays, chromatin immunoprecipitation sequencing, and protein pull-down assay mechanistically revealed that USP28 directly interacted with PPARα (peroxisome proliferator-activated receptor α), deubiquitinating and stabilizing PPARα (Lys152) to promote Mfn2 (mitofusin 2) transcription, thereby impeding mitochondrial morphofunctional defects."
FBXW7-185aa affects USP28
|
4
MiR-216b affects USP28
|
3
CircMED27 affects USP28
|
3
USP28 affects proteolysis
|
3
USP28 activates proteolysis.
|
2
USP28 inhibits proteolysis.
|
1
USP28 inhibits proteolysis. 1 / 1
|
1
reach
"Additionally, our molecular biology experiments validated that the knockdown of USP28 substantially reduced the proliferative and invasive abilities of the HCC cell lines.Conclusions: Our study suggests that USP28 could potentially serve as a biomarker for cancer immunologic infiltration and poor prognosis, with potential applications in developing novel cancer treatment strategies."
eidos
"APC , adenomatous polyposis coli ; DVL , Disheveled ; Fz , frizzled ; GSK3 , glycogen synthase kinase-3 ; LRP , lipoprotein receptor-related ; USP28 , ubiquitin-specific protease 28 As Usp28-deficient mice develop normally , the role of Usp28 in the normal Wnt signaling during embryonic development must be minimal or its absence could be mitigated by unspecified redundant mechanisms , for example , suppressing GSK3beta activity so that TCF7L2 is not ubiquitinated in the first place ."
reach
"A study has proposed a novel mechanism by which USP28 upregulates angiogenesis by antagonizing GSK-3beta (glycogen synthase kinase-3beta) and FBW7 dependent degradation of HIF-1alpha (hypoxia inducible factor-1alpha), a major regulator of angiogenesis, carcinogenesis, and various processes by which cells adapt to hypoxic conditions."
USP28 affects Fbw7α
|
3
USP28 affects E3_Ub_ligase
|
1
2
sparser
"AZ1, VSM, and FT206 bind to USP28 at different overlapping positions inside the same hydrophobic cleft, located at the intersection of the USP-thumb and palm subdomains in the center of the concave part of the USP S1-site, which acts as a binding surface for the globular domain of the distal Ub moiety of the cleaved substrate (Figs. xref and xref )."
sparser
"However, the observation that the three structurally and chemically different compounds AZ1, VSM, and FT206 interact with USP28 in the same cleft, yet exert their inhibitory activity for USP28 and its close homolog USP25 without significantly affecting other DUBs of the USP family, prompted us to further investigate the origin of this selectivity."
USP28 affects Carcinoma, Non-Small-Cell Lung
|
3
USP28 activates Carcinoma, Non-Small-Cell Lung. 3 / 3
|
3
reach
"As a target gene of miR-4295, the high expression of USP28 will promote the occurrence of non-small cell lung cancer,14 promote the proliferation, metastasis, and angiogenesis of cancer cells, and inhibit the apoptosis of cancer cells.34 To sum up, the low expression of miR-4295 will weaken the targeted inhibitory effect on USP28, thus showing a cancer-promoting effect."
USP28 affects Carcinoma, Hepatocellular
|
1
2
USP28 activates Carcinoma, Hepatocellular.
|
2
USP28 activates Carcinoma, Hepatocellular. 2 / 2
|
2
reach
"The USPs family is the largest and most important DUB family, and many of these elements are involved in the occurrence and development of multiple cancers, such as USP1, USP4, USP7, USP22, and USP28, which promote or inhibit the development and progression of colorectal, breast, and hepatocellular carcinomas via deubiquitining the hub genes of cancer-related signaling pathways [10, 11]."
USP28 inhibits Carcinoma, Hepatocellular.
|
1
USP28 inhibits Carcinoma, Hepatocellular. 1 / 1
|
1
eidos
"While reports have indicated that a lack of USP28 could reduce colon cancer in mice [ 114 ] and that USP28 could also be a prognostic marker in bladder [ 115 ] and gastric cancers [ 116 ] , a lack of USP28 promoted liver cancer and correlated with a worse survival of patients with invasive ductal breast carcinoma : Mouse xenograft experiments with USP28-lacking breast cancer cells supported these findings [ 117 ] ."
sparser
"The findings that support this conclusion are the following: (i) the binding of UCK1 to the E3 ligase KLHL2 causes its polyubiquitination at K81 and degradation; (ii) the DUB USP28 binds to UCK1 through interaction with KLHL2 and antagonizes KLHL2-mediated effect on UCK1; (iii) UCK1 deubiquitination by USP28 is dependent on the phosphorylation status of USP28; (iv) USP28 is phosphorylated by 5'-AZA-activated ATM, resulting in disassociation of KLHL2 from USP28 and UCK1 destabilization; (v) ATM also phosphorylates UCK1 at S145, significantly enhancing the KLHL2-UCK1 complex formation; (vi) the knockdown of KLHL2 not only significantly inhibits AML cell proliferation, but also sensitizes AML cells to 5'-AZA-induced apoptosis; and (vii) combinational therapies with 5'-AZA and ectopic USP28 expression enhances the effects of 5'-AZA and induces synergistic lethality at cellular level and in the AML mouse model, which is, however, observed in cells deficient in USP28."
reach
"Previous studies have reported that Pard3 can regulate the stability of Snail1, however there is no clear report on whether Pard3 can regulate the expression of MMP9 by regulating the stability of Snail1.In this study we found that Pard3 silencing activated the NFκB pathway and promoted the transcription of USP28."
sparser
"The findings that support this conclusion are the following: (i) the binding of UCK1 to the E3 ligase KLHL2 causes its polyubiquitination at K81 and degradation; (ii) the DUB USP28 binds to UCK1 through interaction with KLHL2 and antagonizes KLHL2-mediated effect on UCK1; (iii) UCK1 deubiquitination by USP28 is dependent on the phosphorylation status of USP28; (iv) USP28 is phosphorylated by 5'-AZA-activated ATM, resulting in disassociation of KLHL2 from USP28 and UCK1 destabilization; (v) ATM also phosphorylates UCK1 at S145, significantly enhancing the KLHL2-UCK1 complex formation; (vi) the knockdown of KLHL2 not only significantly inhibits AML cell proliferation, but also sensitizes AML cells to 5'-AZA-induced apoptosis; and (vii) combinational therapies with 5'-AZA and ectopic USP28 expression enhances the effects of 5'-AZA and induces synergistic lethality at cellular level and in the AML mouse model, which is, however, observed in cells deficient in USP28."
Fbw7α affects USP28
|
3
E3_Ub_ligase affects USP28
|
1
2
Vemurafenib affects USP28
|
2
MiR-363-3p affects USP28
|
2
USP28 affects vemurafenib
|
2
USP28 activates vemurafenib. 2 / 2
|
2
USP28 affects ubiquitination
|
2
USP28 affects tumor growth
|
2
USP28 affects protein deubiquitination
|
1
1
|
2
USP28 affects cell migration
|
2
USP28 affects cell adhesion
|
2
USP28 inhibits cell adhesion. 2 / 2
|
2
reach
"In contrast, in a detailed study on the function of USP28 in breast cancer XREF_BIBR, Richter et al. found that USP28 deficiency in breast cancer cells enhances conversion toward a more aggressive phenotype by promoting EMT, proliferation, migration, angiogenesis, and decreased adhesion."
USP28 affects Wnt signaling
|
2
eidos
"To explore how USP28 might be involved in HCC development , we undertook a Gene Set Enrichment Analysis and found a significant positive correlation between USP28 expression and the expression of Wnt signaling pathway genes ( Figure 1D ) , suggesting that USP28 might contribute to Wnt signaling ."
USP28 affects Pancreatic Neoplasms
|
2
USP28 activates Pancreatic Neoplasms. 2 / 2
|
2
sparser
"In contrast, a recent study has proposed that ubiquitination of both Pim-1 and Pim-2 is important in regulating the stability of the protein, when under conditions of hypoxia, during hypoxia, deubiquitinase USP28 preferentially binds to Pim-1 and -2 and prevents their degradation [ xref ], suggesting that alternative regulatory mechanisms of Pim kinase degradation may take place under hypoxic conditions."
reach
"AZ1, VSM, and FT206 bind to USP28 at different overlapping positions inside the same hydrophobic cleft, located at the intersection of the USP-thumb and palm subdomains in the center of the concave part of the USP S1-site, which acts as a binding surface for the globular domain of the distal Ub moiety of the cleaved substrate (Figs."
USP28 affects Microcephaly
|
2
USP28 inhibits Microcephaly.
|
1
USP28 inhibits Microcephaly. 1 / 1
|
1
USP28 activates Microcephaly.
|
1
USP28 activates Microcephaly. 1 / 1
|
1
USP28 affects JUN_family
|
2
USP28 affects FT206
|
2
reach
"Computational protonation state analysis with PropKa (Søndergaard et al, 2011) suggests that the proximity of both side chains leads to a doubly protonated H261 thereby rendering engagement in multiple bonds with E366 and with the AZ1 trifluoro-methyl group possible.VSM and FT206 bind to USP28 at similar sites located further towards the wider and open Ub-tail proximal position of the USP28-inhibitor-binding cleft (Fig. 1A,B)."
reach
"AZ1, VSM, and FT206 bind to USP28 at different overlapping positions inside the same hydrophobic cleft, located at the intersection of the USP-thumb and palm subdomains in the center of the concave part of the USP S1-site, which acts as a binding surface for the globular domain of the distal Ub moiety of the cleaved substrate (Figs."
USP28 affects Deubiquitinase
|
2
USP28 affects DNA repair
|
2
USP28 affects DNA damage checkpoint signaling
|
2
USP28 activates DNA damage checkpoint signaling. 2 / 2
|
2
USP28 affects CD44s
|
2
USP28 affects CD44s protein
|
2
USP28 affects CD44 protein stability
|
2
eidos
"ISO attenuated CD44 protein stability by down-regulating USP28 in human BC cells Because ISO treatment not only inhibited endogenous CD44 expression but also reduced ectopic CD44 protein expression in T24T cell , the study next examined if down-regulation of CD44 expression due to ISO was a result of changes in degradation of CD44 protein ."
USP28 affects C-Cdh1
|
2
USP28 affects C-Cdh1 targets
|
2
reach
"The USP25 activity may not be affected upon exposure to an inhibitor blocking the phosphorylation of USP28 on serine 67 and serine It could be another therapeutic option to target the binding between ATM and USP28 and reduce the phosphorylation of USP28, thus decreasing its enzymatic activity in cancer cells with increased DNA damage levels."
| PMC
Radiation, Ionizing affects USP28
|
1
1
Radiation, Ionizing phosphorylates USP28 on S67. 1 / 1
|
1
Radiation, Ionizing leads to the phosphorylation of USP28. 1 / 1
|
1
sparser
"In contrast, a recent study has proposed that ubiquitination of both Pim-1 and Pim-2 is important in regulating the stability of the protein, when under conditions of hypoxia, during hypoxia, deubiquitinase USP28 preferentially binds to Pim-1 and -2 and prevents their degradation [ xref ], suggesting that alternative regulatory mechanisms of Pim kinase degradation may take place under hypoxic conditions."
MYC affects Fbw7α
|
2
JUN_family affects USP28
|
2
Hydrogen-Ion Concentration affects USP28
|
2
FT206 affects USP28
|
2
reach
"Computational protonation state analysis with PropKa (Søndergaard et al, 2011) suggests that the proximity of both side chains leads to a doubly protonated H261 thereby rendering engagement in multiple bonds with E366 and with the AZ1 trifluoro-methyl group possible.VSM and FT206 bind to USP28 at similar sites located further towards the wider and open Ub-tail proximal position of the USP28-inhibitor-binding cleft (Fig. 1A,B)."
reach
"AZ1, VSM, and FT206 bind to USP28 at different overlapping positions inside the same hydrophobic cleft, located at the intersection of the USP-thumb and palm subdomains in the center of the concave part of the USP S1-site, which acts as a binding surface for the globular domain of the distal Ub moiety of the cleaved substrate (Figs."
CD44s affects USP28
|
2
CADPE affects USP28
|
2
Unspecified redundant mechanisms affects USP28
|
1
eidos
"APC , adenomatous polyposis coli ; DVL , Disheveled ; Fz , frizzled ; GSK3 , glycogen synthase kinase-3 ; LRP , lipoprotein receptor-related ; USP28 , ubiquitin-specific protease 28 As Usp28-deficient mice develop normally , the role of Usp28 in the normal Wnt signaling during embryonic development must be minimal or its absence could be mitigated by unspecified redundant mechanisms , for example , suppressing GSK3beta activity so that TCF7L2 is not ubiquitinated in the first place ."
Signal transduction affects USP28
|
1
Signal transduction activates USP28. 1 / 1
|
1
ShRNA-mediated affects USP28
|
1
Rigosertib sodium affects USP28
|
1
Rigosertib sodium activates mutated USP28. 1 / 1
|
1
MiR-655-3p affects USP28
|
1
MiR-143-3p affects USP28
|
1
CircRNA FBXW7 affects USP28
|
1
Caffeic acid affects USP28
|
1
Caffeic acid inhibits USP28. 1 / 1
|
1
VSM affects USP28
|
1
reach
"AZ1, VSM, and FT206 bind to USP28 at different overlapping positions inside the same hydrophobic cleft, located at the intersection of the USP-thumb and palm subdomains in the center of the concave part of the USP S1-site, which acts as a binding surface for the globular domain of the distal Ub moiety of the cleaved substrate (Figs."
UbV.USP28 affects USP28
|
1
UbV.28 affects USP28
|
1
USP28 affects ΔFBXO42
|
1
USP28 affects Δ
|
1
USP28 affects viability gastric cancer cells
|
1
USP28 affects ubiquitination transcription 7-like TCF7L2
|
1
USP28 affects ubiquitination LEF1
|
1
USP28 affects ub-K119-H2A
|
1
USP28 affects turnover
|
1
USP28 affects tetraubiquitin
|
1
USP28 affects stability PIM1 hypoxia
|
1
USP28 affects stability CHK2
|
1
USP28 affects radiosensitivity esophageal cancer cells
|
1
USP28 affects p53_family
|
1
USP28 deubiquitinates p53_family. 1 / 1
|
1
USP28 affects p-Chk1 protein
|
1
USP28 affects mitotic cell cycle
|
1
USP28 activates mitotic cell cycle. 1 / 1
|
1
USP28 affects miR-500a-5p
|
1
USP28 affects melanoma cell resistance
|
1
USP28 affects localization
|
1
USP28 activates localization. 1 / 1
|
1
USP28 affects lifespans
|
1
USP28 affects lenvatinib
|
1
USP28 inhibits lenvatinib. 1 / 1
|
1
USP28 affects growth lung cancer cells
|
1
USP28 affects fibrosarcoma-ERK
|
1
USP28 affects embryo development
|
1
USP28 activates embryo development. 1 / 1
|
1
USP28 affects different isoforms
|
1
USP28 affects cellular catabolic process
|
1
USP28 activates cellular catabolic process. 1 / 1
|
1
USP28 affects cell viability HGC-27 cells
|
1
USP28 affects aerobic glycolysis colorectal cancer
|
1
USP28 affects accumulate HIF-1alpha protein cells
|
1
USP28 affects Wnt/β-catenin
|
1
USP28 affects VSM
|
1
reach
"AZ1, VSM, and FT206 bind to USP28 at different overlapping positions inside the same hydrophobic cleft, located at the intersection of the USP-thumb and palm subdomains in the center of the concave part of the USP S1-site, which acts as a binding surface for the globular domain of the distal Ub moiety of the cleaved substrate (Figs."
USP28 affects UbV.28
|
1
USP28 affects USP
|
1
USP28 affects Snail1
|
1
reach
"RNA sequencing, immunoprecipitation and mass spectrometry analysis, chromatin immunoprecipitation assays, chromatin immunoprecipitation sequencing, and protein pull-down assay mechanistically revealed that USP28 directly interacted with PPARα (peroxisome proliferator-activated receptor α), deubiquitinating and stabilizing PPARα (Lys152) to promote Mfn2 (mitofusin 2) transcription, thereby impeding mitochondrial morphofunctional defects."
reach
"More interestingly, Plk3 also destabilizes SIAH2 in a kinase activity dependent manner.55 Thus, a mutual regulatory mechanism exists between Plk3 and SIAH2, which may functions to fine-tune the HIF-1 signaling.USP28, a deubiquitinase that suppresses the stability of MYC and HIF-1a,36,60,61 also appears to indirectly contribute to suppression of Plk3 by hypoxia and nickel.55 It has been shown that USP28 can be suppressed by nickel via HIF-, the ubiquitin-proteasome system-, and DNA methylation dependent mechanisms.62 USP28 prevents the suppression of Plk3 by nickel, suggests that suppression of Plk3 deubiquitination by USP28 in response to nickel could contribute to the elevated degradation of Plk3 by the ubiquitin-proteasome system."
USP28 affects PIM1/2
|
1
USP28 affects Neoplastic Stem Cells
|
1
USP28 activates Neoplastic Stem Cells. 1 / 1
|
1
reach
"As K48-linked ubiquitination of NBS1 by SKP2 E3 ligase also occurs in cells with intact RECQL4 helicase and overexpression of USP28 reduces the ubiquitination of NBS1, these results suggest that there may be a novel control mechanism that plays an important role in the DSB response by ubiquitination and deubiquitination of NBS1."
USP28 affects MiR-500a-5p
|
1
USP28 affects MAPK cascade
|
1
USP28 inhibits MAPK cascade. 1 / 1
|
1
reach
"Prior work has also suggested that USP28 may contribute to the basal phenotype, as the downregulation of USP28 led to decrease of the basal marker CK14, in association with a shift from basal to luminal cellular morphology [54], and in lung cancer the deletion of USP28 reduces the number of lesions with expression of CK5 [55]."
USP28 affects ISO-induced BC cell sphere
|
1
USP28 affects Hypertrophy
|
1
USP28 activates Hypertrophy. 1 / 1
|
1
USP28 affects Hemagglutinins
|
1
reach
"A study has proposed a novel mechanism by which USP28 upregulates angiogenesis by antagonizing GSK-3beta (glycogen synthase kinase-3beta) and FBW7 dependent degradation of HIF-1alpha (hypoxia inducible factor-1alpha), a major regulator of angiogenesis, carcinogenesis, and various processes by which cells adapt to hypoxic conditions."
USP28 affects Forkhead box
|
1
reach
"In another study, a reduction in G0/G1-phase cells and an increase in S-phase cells were observed in pancreatic cancer cells with ectopic expression of USP28, and this advancement in cell proliferation was mediated by the deubiquitination of Forkhead box M1 (FOXM1), which is induced by USP28 [4]."
USP28 affects FBW7-E3 ligase
|
1
USP28 affects E3-ligases
|
1
USP28 affects Carcinoma, Squamous Cell
|
1
USP28 activates Carcinoma, Squamous Cell. 1 / 1
|
1
USP28 affects Breast Neoplasms
|
1
USP28 inhibits Breast Neoplasms. 1 / 1
|
1
USP28 affects BRAF protein
|
1
USP affects USP28
|
1
UCK1 affects Hemagglutinins
|
1
Ten-eleven translocation1 affects USP28
|
1
Streptoglutarimide H affects USP28
|
1
PIM1/2 affects USP28
|
1
MiR-500a-5p affects USP28
|
1
Hemagglutinins affects USP28
|
1
E3_Ub_ligase affects TP53
|
1
E3-ligases affects USP28
|
1
CircMED27 affects USP28
|
1