IndraLab
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"For example, gankyrin competes with p16 for binding to CDK4, thus blocking the CDK4-inhibitory activity of p16; p34 SEI1 (SERTAD1) is able to bind to the CDK4-cyclin D1 complex and enhance the latter 's kinase activity; BMI1 (B lymphoma Mo-MLV insertion region 1 homolog, a polycomb ring finger protein) down-regulates the expression of p16 (CDKN2A) and p15 (CDKN2B) genes, which consequently promotes CDK4 mediated phosphorylation of pRb."
sparser
"Nuclear cyclin D1, in turn, together with its partners CDK4 and CDK6 phosphorylates pRB with subsequent dramatic increase in cyclin A and elevation of CDK2 causing further phosphorylation of pRB, coincident with progression of epithelial cells towards S-phase of the cell cycle, thus DNA synthesis [ xref ]."
sparser
"The eukaryotic cell cycle depends on the sequential formation and activation of different cyclin-dependent kinase (CDK) complexes. xref , xref In response to the mitogenic/oncogenic signaling, cell cycle commitment at the restriction (R) point in the G1 phase is initiated by inactivating phosphorylations of the central cell cycle/tumor suppressor Rb by CDK4 and CDK6. xref , xref , xref Rb phosphorylation is maintained by a positive-feedback loop linking Rb to E2F-dependent transcription of cyclin E, that in turn activates CDK2 and leads to further phosphorylation of Rb. xref This feedback, coupled with self-induction of E2F and mutual inhibition between cyclin E-CDK2 and p27 Kip1 , generates a bistable Rb-E2F switch that converts graded mitogen inputs into all-or-none E2F responses and finally into the cell cycle commitment. xref Because the frequent deregulation of CDK4 in cancer often leads to addiction to its activity, CDK4 is emerging as a particularly promising therapeutic target. xref , xref , xref , xref Specific CDK4/6 inhibitors are being tested against most cancers xref , xref and PD0332991 (Palbociclib) received a first approval by the FDA as a first-line treatment combined with endocrine therapy of advanced breast cancers. xref "
rlimsp
"PRb is a physiological target of both cdk4 and cdk2 [17]. If the primary function of one or both of these kinases in MCF-7 cells is to phosphorylate pRb, then cells in which pRb family members are inactivated by PyLT should no longer require the activity of that kinase for proliferation."
sparser
"Deletion of this potential helix (ΔHelix) or disruption of this helix by proline substitution (Q899P or A902P) drastically reduced Rb phosphorylation by cyclin D-Cdk4,6, which was comparable to the phosphorylation of an Rb variant (ΔCdk) lacking all 14 accessible Cdk phosphorylation sites ( xref , xref , xref )."
sparser
"The cyclin-dependent kinase 4 (CDK4)/cyclin D1 complex phosphorylates the RB1 protein, thereby increasing release of the E2F1 transcription factor that activates genes involved in the G1 to S transition. xref p16 INK4a binds to CDK4, inhibits the CDK4/cyclin D1 complex, and thus inhibits the G1 to S transition. xref Inactivating mutations in RB1 or the upstream factorp16 INK4a (also called inhibitor of CDK4a), or activating mutations in the downstream factors CDK4 or cyclin D , cause dysregulated control of E2F1."
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"The regulatory pathway controlling G1-S is the Rb/E2F pathway : in the presence of extracellular growth-stimulatory signals, cyclinD1 and its kinase partner cdk4 form an activated complex and phosphorylate Rb and Rb family members, thus inactivating Rb and allowing E2F/DP transcription factors to exert their transactivation activity."
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"Disruption of the CDK4-pRb pathway occurs frequently in a variety of human cancers, and in many cases, the underlying molecular mechanisms involve the activation of CDK4 gene as well as CDK4 promoting oncogenes or the inactivation of CDK4 inhibiting tumor suppressor genes or both, resulting in aberrant CDK4 mediated phosphorylation of pRb."
sparser
"This is consistent with previous report that CCND3 partially compensates for loss of CCND2 in mouse B-lymphocytes by Rb phosphorylation on Cdk4 specific sites [ xref ] Additionally, the remaining D-cyclins can increase when a tissue-specific D-cyclin is eliminated during early murine embryonic development [ xref ]."
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"Furthermore, unlike cdk-4 overexpression, which alone is unable to either measurably phosphorylate pRb or activate beta-cell replication (XREF_FIG B), cdk-6 overexpression alone is able to accomplish both of these outcomes, presumably by combining with endogenous beta-cell d-type cyclins."
sparser
"Induction of miR-21 and miR-181b expression in sepsis Gr1 + CD11b + MDSCs is mediated by Rb phosphorylation by the cyclin D1–cdk4 protein complex. xref In these cells, phosphorylated Rb binds to and sequesters the C/EBPa protein, leading to Stat3 and C/EBPb binding to and activating of the miR-21 and miR-181b promoters. xref The Gr1 + CD11b + cells from the NFI-A conditional knockout mice did not express miR-21 and miR-181b ( xref )."
sparser
"We propose that these partially active Cdk4 complexes partially phosphorylate the retinoblastoma protein (Rb), resulting in partial activation of E2F transcription factors (E2Fs) which stimulates expression of cyclins E and A. These cyclins bind and activate Cdk2 which fully phosphorylates Rb, fully activates the E2Fs, and drives cells into S phase."
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"CDK4 and 6 are substrate specific and phosphorylate only Rb, whereas cyclin E-CDK2 has a broader range of specificity to phosphorylate histone H1, Rb, p27 and Kip1 and possibly other substrates that help trigger the firing of replication origins, centrosome duplication and histone biosynthesis [XREF_BIBR, XREF_BIBR, XREF_BIBR]."
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"Immunoblots utilizing an antibody against the 110-kDa retinoblastoma protein (Rb), a downstream phosphorylation target of the cyclin D1/cyclin dependent kinase 4 (cdk4) complex, showed reduced electrophoretic mobility of this protein as early as 8 h after PDGF treatment, suggesting phosphorylation of Rb by the cyclin D1 and cdk4 dimer in vivo."
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"Moreover, BPS induced Rb phosphorylation and cell cycle progression were prevented by the ERalpha inhibitor ICI 182,780 and methylpiperidino pyrazole, as well as cyclin dependent kinase 4 (CDK4) and CDK6 inhibitor PD 0332991, indicating that the underlying mechanisms involve ERalpha dependent pathways but also mediated by cyclin D-CDK4/6."
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"Our past studies have established a sequential pathway for neuron death caused by NGF deprivation and Abeta exposure in which : 1) activated Cdk4 phosphorylates members of Rb family of transcription regulating proteins; 2) such phosphorylation leads to dissociation of repressor complexes containing Rb family members, E2F transcription factor proteins and chromatin modifiers; 3) there is consequent derepression and elevated expression of E2F responsive genes including the transcription factors B- and C-Myb; and 4) the induced mybs activate transcription of the gene encoding the pro apoptotic BH3-only protein Bim."
sparser
"Given the critical role of RB1 inactivation in CRPC [ xref ], tumors with low CSK may inactivate the RB1 pathway through other means such as overexpression of cyclin D or downregulation of p15 and p16 [ xref , xref , xref ], which lead to CDK4-dependent RB1 phosphorylation and inactivation of its E2F1 repressive activity."
sparser
"The cyclin-dependent kinase inhibitor 2A locus ( CDKN2A ) at chromosome 9p21.3 encodes both the p16(INK4A) and p14(ARF) proteins, which regulate the critical Rb and p53 cell cycle regulatory pathways, respectively. xref During the cell cycle, these proteins regulate cell cycle progression, for example p16(INK4A) plays an essential role in inducing G1 cell cycle arrest by inhibiting the phosphorylation of the Rb protein by the cyclin-dependent kinases CDK4 and CDK6. xref Other tumor suppressor genes such CDKN2B and MTAP are located near CDKN2A at 9p21.3."
sparser
"On the other hand, CDK4 phosphorylates the RB (retinoblastoma protein), which inhibits its interaction with E2F transcription factor, allowing it to escape the G1-S checkpoint.[ xref ]However, we must keep in mind that MDM2 expression may appear not only in tumor cells, but also in histocytes, which is observed in lipoma with degenerative changes.[ xref ]Recent studies showed the utility of a combination of MDM2, CDK4, and p16 (cyclin-dependent kinase inhibitor 2A) as useful markers for detecting ALT/WDL and dedifferentiated liposarcoma.[ xref ]p16 binds CDK4 and inhibits cell cycle progression and its level is supposed to be correlated with the level of MDM2 and CDK4.[ xref ]These immunohistochemical examinations help provide a more accurate differential diagnosis, especially when a molecular diagnosis, which uses MDM2 amplification assessed by fluorescence in situ hybridization, is not available.[ xref ]Thway et al found that expression of MDM2 tended to be weak but that of CDK4 and p16 was mostly moderate to strong in ALT/WDL,[ xref ]which was also observed in our case."
sparser
"In this model, HBP1 binds to the CCND1 and CCND3 promoters and activates their transcription, HBP1 also binds to p16 INK4A promoter, but does not change its expression, though it does remove the inhibitory effect of p16 on CDK4, thus, CCND1-CDK4 and CCND3-CDK6 complexes facilitate the phosphorylation of p107 and pRB, respectively."
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"These findings suggest that phosphorylation of pRb by CDK4 is not critical in the carcinogenesis or in the establishment of HPV positive cervical cancer cell lines, since HPV E6 or E7 viral transforming proteins inactivate p53 and pRb tumor suppressor protein function, resulting in deregulated progression of the cell cycle."
rlimsp
"(v) Lysates of Spodoptera frugiperda Sf9 cells doubly infected with baculoviruses genetically engineered to express cyclin D3 and cyclin-dependent kinase 4 (CDK4) phosphorylated GST fused to retinoblastoma protein (GST-pRb) but did not phosphorylate the GST-alpha0(20-241) or GST-alpha0(543-768) fusion protein or immunoprecipitated ICP0 proteins."
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"While the expression levels of Cyclin-Dependent Kinases remain fairly constant, their activities are highly regulated.DNA synthesis phase (S phase) occurs when the protein RB is phosphorylated by active CDK4 or CDK6, which releases the transcription factor E2F1 from RB and allows the free E2F1 to bind and activate E2F responsive genes necessary for progression to S phase."
| PMC
sparser
"Sequential phosphorylation of pRB by cyclin D-CDK4 and cyclin E-CDK2 in G 1 phase inactivates its growth-inhibitory function allowing cell cycle progression.( xref ) Nuclear p27 functions to inhibit CDK2 and CDK4 activity resulting in hypophosphorylation of pRB and inhibition of cell cycle progression."
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"The first cyclin dependent kinases (CDKs) activated in response to mitogenic stimulation are CDK4 and CDK6 that, after binding with cyclin D, promote retinoblastoma protein (Rb) hyperphosphorylation and inactivation with the consequent release of the transcription factor E2F, thus prompting cell cycle progression through the S phase.The inhibition of cell cycle regulators such as CDK4 and CDK6 has become a new therapeutic frontier for the treatment of breast cancer (BC)."
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"This inhibition was attenuated when SNAP was added after 9-12 h. SNAP inhibited the activity of cyclin dependent kinase 2 (Cdk2) and phosphorylation of the retinoblastoma protein, both of which usually increased from about 9 h, whereas it did not inhibit the activities of cyclin D associated kinase (s), Cdk4, and Cdk6, which normally increased from 0-3 h. Although SNAP reduced the mRNA levels of cyclins E and A, it neither reduced their protein levels nor impaired their association with Cdk2."
sparser
"The Rb dilution mechanism does not require progressive phosphorylation of Rb by cyclin D-Cdk4,6 in G 1 and is therefore compatible with recent reports showing constant hypophosphorylation of Rb through most of G 1 ( xref ) and the ability of cells to initiate the G 1 /S transition before Rb hyperphosphorylation in the absence of cyclin D-Cdk4,6 activity ( xref )."
sparser
"These findings suggest that phosphorylation of pRb by CDK4 is not critical in the carcinogenesis or in the establishment of HPV-positive cervical cancer cell lines, since HPV E6 or E7 viral-transforming proteins inactivate p53 and pRb tumor suppressor protein function, resulting in deregulated progression of the cell cycle."
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"The cell cycle commitment at the restriction (R) point in G1 phase is initiated by inactivating phosphorylations of the central cell cycle and tumor suppressor pRb by CDK4 and CDK6, which are activated by D-type cyclins induced by mitogenic and oncogenic signaling XREF_BIBR - XREF_BIBR."
sparser
"In differentiated cells such as mammalian muscle, cell cycle arrest is not relieved by serum stimulation presumably because the kinases such as CDK4 that normally phosphorylate Rb in response to mitogens are inhibited from doing so by CDIs present at high levels in these cells ( xref ; xref )."
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"However, the findings of Chung et al. (2019) are in apparent conflict with compelling evidence from Narasimha et al. (2014) that CDK4,6/cyclin D is only able to monophosphorylate RB and that hyperphosphorylation does not occur until after the appearance of CDK2/Cyclin E activity in “late” G1."
sparser
"Cyclin D1 is one of the main regulatory molecules of the cell cycle.[ xref ] It belongs to the family of D-type cyclins, which regulate cell cycle progression from G1 to S phase by regulating the activity of cyclin-dependent kinases (CDKs).[ xref ] Cyclin D1 and its close relatives, cyclin D2 and cyclin D3, all appear to associate with the same kinase partners.[ xref ] Binding of cyclin D1 to CDK4 and CDK6 induces hyperphosphorylation of retinoblastoma protein (Rb)."
sparser
"In a normal cell cycle, during the early G1 phase, retinoblastoma protein (pRb) is hypophosphorylated, while in the later phase of G1, in order for a cell to enter the S phase, pRb is progressively hyperphosphorylated by CDK4 and CDK6 (Satyanarayana and Rudolph, 2004; Li et al., 2011)."
sparser
"In normal cells, pRB phosphorylation by cdk4 and/or cdk6/cyclin D complexes in G1 results in the disruption and/or functional inactivation of the pRB/E2F transcriptional repressor complexes, and dissociated E2Fs act as transcriptional activators of genes that are rate limiting for S-phase entry and progression (reviewed in xref )."
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"Although pretreatment with TCDD suppressed CDK2 kinase activity and increased the association of CDK2 with negative regulatory proteins p21Cip1 and p27Kip1, a corresponding increase in CDK4 and cyclin D1 association and CDK4 activity which culminated in enhanced phosphorylation of retinoblastoma protein, consistent with the increased proliferative response."
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"In a normal cell cycle, during the early G1 phase, retinoblastoma protein (pRb) is hypophosphorylated, while in the later phase of G1, in order for a cell to enter the S phase, pRb is progressively hyperphosphorylated by CDK4 and CDK6 (Satyanarayana and Rudolph, 2004; Li et al., 2011)."
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"To identify the G1 kinase in colorectal carcinoma, we have shown that knockdown of CDK6 but not CDK4 markedly reduces RB phosphorylation and inhibits the growth of colorectal carcinoma cells, suggesting for the first time that CDK6-RB axis is crucial in the growth of the carcinoma and targeting of the CDK6-RB axis may provide a novel therapeutic strategy in the treatment of colorectal carcinoma."
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"Tucker and co-workers originally showed that PDGF induces the resorption of the cilium and the competence of cells to replicate their DNA in cultures of growth arrested fibroblasts [XREF_BIBR], and activation of PDGFRalphaalpha in the fibroblast primary cilium leads to cyclin dependent kinase 4 (Cdk4)-mediated phosphorylation of retinoblastoma protein (Rb) [XREF_BIBR], which marks the cell cycle G 1 -S phase transition."
sparser
"Therefore, it is conceivable to expect that HTLV-1 infection and Tax expression inactivates both p16ink4 and p15ink4 resulting in activation of Cdk4, which subsequently phosphorylates Rb protein to releases E2F. The released E2F then activates transcription of various genes required for compelling cells into a G1-S transition and promotes abnormal cell cycles."
sparser
"One example of this feed forward loop can be seen in late G 1 progression following initial disassociation of Cdk4 phosphorylated RB from E2F which results in increasing transcriptional activity and correlating expression of cyclin E. Increased availability of cyclin E binds to and activates Cdk2 in a complex that further phosphorylates RB, thereby increasing E2F promoter activity."
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"CDK4 is a member of the Ser/Thr protein kinase family, required for the cell cycle transition from the G1 to S-phase [XREF_BIBR]; thus, CDK4 phosphorylates the Rb gene product leading to its inactivation and the release of proteins required for cell cycle progression, at the same time it also down-regulates TP53 [XREF_BIBR]."
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"These findings suggest that phosphorylation of pRb by CDK4 is not critical in the carcinogenesis or in the establishment of HPV positive cervical cancer cell lines, since the HPV viral transforming proteins E6 or E7 inactivate p53 and pRb tumor suppressor protein function, resulting in deregulated progression of the cell cycle."
sparser
"In G1 phase, phosphorylating of Rb is initiated by activated Cdk4 and Cdk6 complexes with D-type cyclins (Cyclin D) and then Rb phosphorylation is completed by Cdk2/cyclin E complexes in late G1 phase [ xref , xref ]. xref shows that the nuclear expressions of Cdk2 and Cdk4 and the expressions of their binding partners, such as cyclin E and Cyclin D ( xref and xref ) were decreased by SNAC treatment."
sparser
"Protein p16, also called Cyclin-Dependent Kinase Inhibitor 2A (CDKN2A), is an inhibitor of the cyclin dependent kinases CDK4 and CDK6 which phosphorylate the retinoblastoma protein pRB (the key protein control of the cell cycle restriction point in G1 phase) and allow the progression from G1 phase to S phase [ xref ]."
sparser
"Cyclin-dependent kinases (CDKs) regulate cell cycle progression, and CDK4 and CDK6 induce hyperphosphorylation of the retinoblastoma protein, causing the progression of tumor cells from the G1 checkpoint to the S phase of the cell cycle. xref , xref , xref The development of endocrine resistance in breast cancer is associated with the deregulation of the cyclin D/CDK4-6/retinoblastoma pathway. xref , xref Cyclin D is also a key target for estrogen-induced cell proliferation through the estrogen receptor."
sparser
"Tucker and co-workers originally showed that PDGF induces the resorption of the cilium and the competence of cells to replicate their DNA in cultures of growth-arrested fibroblasts [ xref ], and activation of PDGFRαα in the fibroblast primary cilium leads to cyclin-dependent kinase 4 (Cdk4)-mediated phosphorylation of retinoblastoma protein (Rb) [ xref ], which marks the cell cycle G 1 –S phase transition."
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"Cyclin D1 is a key cell cycle regulatory protein, playing a critical role in the G1-to-S transition of the cell cycle progression through binding to cyclin dependent kinase 4 (CDK4) to phosphorylate and inactivate the retinoblastoma protein (pRb), heterozygous deletion of which occurs in ~ 50% of human muscle-invasive BC."
sparser
"We further revealed the molecular mechanism by which nuclear-localized GHR regulates MSCs proliferation, and found that nuclear-targeted GHR enhanced the phosphorylation of STAT5, and the activated STAT5 initiates the transcription of CyclinD1, after which, the complex of CyclinD1 and CDK4 further phosphorylates Rb, and the activated Rb releases E2F1, the released E2F1 ultimately realizes the biological function of GH promoting cell proliferation."
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"Tucker and co-workers originally showed that PDGF induces the resorption of the cilium and the competence of cells to replicate their DNA in cultures of growth arrested fibroblasts [XREF_BIBR], and activation of PDGFRalphaalpha in the fibroblast primary cilium leads to cyclin dependent kinase 4 (Cdk4)-mediated phosphorylation of retinoblastoma protein (Rb) [XREF_BIBR], which marks the cell cycle G 1 -S phase transition."
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"The combined kinase functions of early G 1 cyclin-D and CDK4 or 6 and late G 1 cyclin-E and CDK2 serve to phosphorylate the retinoblastoma protein (RB), allowing E2F transcription factors to control downstream cyclin expression (for example, cyclin A) required for S-phase transition."
rlimsp
"These findings suggest that phosphorylation of pRb by CDK4 is not critical in the carcinogenesis or in the establishment of HPV-positive cervical cancer cell lines, since HPV E6 or E7 viral-transforming proteins inactivate p53 and pRb tumor suppressor protein function, resulting in deregulated progression of the cell cycle."
sparser
"It encodes a transmembrane protein with structural similarity to neural cell adhesion molecule. xref DCC promoter region has been found to be hypermethylated in multiple tumor types. xref , xref , xref p16 is a recognized tumor suppressor which induces G 1 cell cycle arrest by inhibiting the phosphorylation of pRb by the cyclin-dependent kinases CDK4 and CDK6. xref EDNRB is a non-selective G protein-coupled receptor which activates phosphatidylinositol-calcium second messenger system and is proposed to negatively regulate the activity of ET-1 which includes ET-1 clearance, inhibition of ET-1 secretion, and activation of signaling transduction pathways that counter-regulate ET-1. xref ET A R-mediated mitogenic and additive proliferative effect of ET-1 may be enhanced by methylation inactivation of the EDNRB gene and the loss of its unique negative regulatory functions. xref It has been demonstrated to be hypermethylated in some types of tumors viz., nasopharyngeal, prostate, bladder, hepatocellular, lung, esophageal. xref – xref Kinesin superfamily proteins (KIFs) constitute a large superfamily of microtubule-dependent proteins that transport membranous organelles and macromolecules fundamental for cellular functions along microtubules. xref KIF1A is an anterograde motor protein that transports membranous organelles along axonal microtubules."
sparser
"Through mechanisms that are not well understood, CDK4/gankyrin assembly increases the extent to which CDK4 phosphorylates retinoblastoma protein (Rb).( xref , xref ) Increased cellular levels of phosphorylated Rb (pRb) leads to over-activation of E2F transcription factors and aberrant E2F-dependent transcription ( xref ).( xref ) Additionally, gankyrin can bind to the E3 ubiquitin ligase MDM2, and in doing so, increases the extent to which p53 is ubiquitinated/polyubiquitinated ( xref ).( xref , xref ) Increased ubiquitination/polybuiquitination of p53 by the MDM2/gankyrin complex ultimately leads to p53 degradation in the proteasome and suppression of p53-dependent apoptosis."