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TP53 activates TP53. 898 / 1178
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"The inducible phosphorylation of p53, especially at the N-terminal serine and threonine residues, is assumed to change the conformation of this protein, thereby prevents the p53-MDM2 interaction and consequently disrupts MDM2 dependent degradation and promotes the accumulation of p53."
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"iASPP ( 295-828 ) preferentially inhibits p53 over NF-kappaBp65 Based on the fact that iASPP ( 295-828 ) acts as a double-edged sword in regulating apoptosis , by inhibiting either p53 or NF-kappaBp65 , we next investigated whether iASPP ( 295-828 ) preferentially regulates either of these two targets ."
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"STZ treatment inhibits phosphorylation of p53 on Thr 155, which is induced by COP9 signalosome (CSN) and is required for p53 degradation, and results in increased GlcNAcylation on Ser 149, thus, blocking p53 from being phosphorylated and degraded by ubiquitin-proteasomal mechanism."
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"XREF_BIBR Thus, since the E3 ligase activity of MDM2 is not affected by Nutlin, the remaining low levels of complex formation between MDM2 and p53, although insufficient for mediating p53 polyubiquitination and destabilization, is sufficient for mediating p53 monoubiquitination which is known to promote p53 trafficking to mitochondria."
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"Although Bortezomib increased the levels of p53 and increased the expression of pro apoptotic target genes in ERalpha+ breast cancer cells harboring wild-type p53, Bortezomib also exerts anti-tumoral effects on ERalpha+ breast cancer cells through suppression of ERalpha expression and inhibition of PI3K/Akt/mammalian target of rapamycin (mTOR) and ERK signaling independently of functional p53."
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"These data suggest that p68, p53 and 133p53alpha may form part of a complex feedback mechanism to regulate the expression of Delta133p53, with consequent modification of p53 mediated transcription, and may modulate the function of p53 in breast and other cancers that harbour wild-type p53."
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"Phosphorylation of p53 by ATM or ATR leads to increased DNA binding and transcriptional activation of p53 target genes important for cell cycle arrest, while additional post-translational modifications of p53, including lysine acetylation, further activate genes important for apoptosis and autophagy [XREF_BIBR]."
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"We assume that the deactivation rate of the single gene copy is constant, and that the deactivation events are independent, so that : As far as the activation rates are concerned, we recall that the p53 protein is a transcription factor for both Mdm2 and PTEN XREF_BIBR, and that p53 phosphorylation enhances p53 activity in transcription XREF_BIBR."
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"A major mechanism for functional inactivation of p53 is through overexpression of two chief p53 suppressors, MDM2 and MDMX, which work together to inactivate p53 by directly interacting with p53, inhibiting its transcriptional activity and mediating its ubiquitin dependent degradation."
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"The investigators hypothesize that, by inhibiting MDM2 expression, the MDM2 oncoprotein level will be reduced and the MDM2 negative feedback inhibition of p53 will be diminished, resulting in a significant increase of functional p53 levels that will modulate p53 mediated therapeutic effects."
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"Phosphorylation of p53 in response to stress disrupts its binding with HDM2, blocks ubiquitination and proteolysis, and results in a rapid increase in p53 protein levels, allowing p53 to enter the nucleus, bind to DNA, and induce expression of genes controlling cell cycle, apoptosis, DNA repair, and cellular senescence [XREF_BIBR]."
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"Therefore, we summarized the results revealing that low-dose and long-term treatment with SAHA in GBM spheroids induces p53 phosphorylation at Ser33 causing an increase in cell cycle checkpoint activation, but SAHA in high-dose and short-term treatment induces p53 phosphorylation at Ser15 leading to p53 dependent apoptosis in U87MG spheroids, and even induces p53 independent apoptosis in U373MG spheroids."
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"Despite the complex regulation of p53 in CML cells, our studies show that enhanced p53 acetylation following SIRT1 inhibition is sufficient to increase p53 transcriptional activity in CML progenitor cells, that p53 deacetylation is an important protective mechanism for CML LSC following TKI treatment."
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"In vivo expression of p53 in the sensorimotor cortex rescued and enhanced the sprouting potential of the CST in p53 (-/-) mice, while, similarly, p53 expression in p53 (-/-) cultured cortical neurons rescued a defect in neurite outgrowth, suggesting a direct role for p53 in regulating the intrinsic sprouting ability of CNS neurons."
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"This implies that such a heterozygous state of p53 is often transient during cancer progression and there is a selective force driving the inactivation of the remaining wild-type p53 allele in cancers, and also suggests that the dominant negative effect of mutp53 is not sufficient to completely inactivate the remaining wild-type p53 allele in majority of cancers."
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"Despite little evidence that p53 contributes to normal mammalian development, enforced p53 expression triggers differentiation in certain p53 deficient tumor cells and, conversely, p53 loss has been described as a factor that promotes de-differentiation during glioblastoma development in mice."
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"Furthermore, our result also demonstrated that knockdown of NR5A2 decreased the expression of p53-related genes (e.g., GADD45A, DDB2, SERPINE1, SHISA5, STEAP3, BAX, RRM2B, CD82) associated with p53 pathway (14), which could be attenuated by TP53 silencing in FaDu cells (
Supplementary Figure 3C
)."
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"Interestingly, p85alpha is also required for the autoacetylation of p53 associated p300 (XREF_FIG), which events may be helpful to upregulate HATs activity of p300 and then increase p53 transcriptional activity by promoting histone acetylation in the vicinity of p53-RE, and therefore altering the chromatin structure for the access of p53."
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"Our results showed that TRIM72 enhances the overall ubiquitination activity of RLE cells that is linked to bleo induced p53 upregulation as well as Ser 15 phosphorylation of p53, suggesting that these post-translational modifications are the target mechanisms of TRIM72 modulation of p53, collectively leading to suppressed transcription of p53 target genes."
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"A number of TP53 missense mutations produce full-length p53 proteins that frequently have a prolonged half-life with accumulation of inactive protein, whereas frameshift mutations do not usually lead to accumulation of p53, and nonsense mutations generally result in an unstable protein."
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"Activation of AKT-1 and its other isoforms have been implicated in cell survival pathways in human cancer cells through its phosphorylation of the ubiquitin ligase MDM2, which in turn promotes the MDM2 mediated ubiquitination and degradation of p53, which disrupts the p53 intrinsic apoptotic program."
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"Interestingly, while MDH1 does not interfere with the p53 and MDM2 interaction, overexpression and depletion experiments show that MDH1 inhibits p53 ubiquitylation and prevents MDM2 dependent cytoplasmic retention of p53, thereby promoting apoptosis in response to glucose starvation 61."
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"23 Acetylation of p53 activates its sequence specific DNA binding and its transcriptional activity, as well as enhances the stability of the p53 protein, owing to the mutual exclusion of acetylation and ubiquitination, 25 therefore, resulting in p53 dependent gene activation in response to cellular stress."
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"Second, while previous studies have produced a correlation between Sirt1 and p53 in promoting the differentiation of hESCs [XREF_BIBR], our studies provide the first physiological evidence to prove that the acetylation of p53 at K120 and K164, which is inhibited by Sirt1, is required to activate p53 response to induce hESC differentiation."
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"Quantification of these experiments showed that TFEB-S211A expression significantly increased the relative p53 levels at all cycloheximide chase time points from 15 min to 90 min, while TFE3-S321A expression significantly increased the relative p53 after 30 min cycloheximide chase (Figure 5E)."
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"This conclusion is also supported by the fact that in gliomas there was an increase in MDM2, which is a protein responsible for degrading p53, XREF_BIBR - XREF_BIBR while in adenocarcinomas there was an increase in the level of p53, which would be likely to trigger p53 dependent apoptosis in these cells."
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"PGAM1 activity has been reported to be upregulated in many cancers, including hepatocellular carcinoma and colorectal cancer XREF_BIBR, XREF_BIBR, probably due to increased PGAM1 gene expression resulting from loss of TP53, as PGAM1 is a negative transcription target of TP53 XREF_BIBR - XREF_BIBR."
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"Overexpression of apoptosis stimulating protein 2 of p53 (ASPP2) induces apoptotic cell death in hepatoma cells (e.g. HepG2 cells) by enhancing the transactivation activity of p53, but long-term ASPP2 overexpression fails to induce more apoptosis since activation of the epidermal growth factor and epidermal growth factor receptor and SOS1 pathway impairs the pro apoptotic role of ASPP2."
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"Additionally, the disruption of the interaction between p53 and Hdm2 inhibited the Dex-mediated ubiquitination of GRα and p53 within human umbilical endothelial cells, suggesting that the Dex-mediated downregulation of GRα requires the association of GRα with p53, the association of p53 with Hdm2 and the ligase activity of Hdm2."
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"Human DYRK2 is a critical component in the Hedgehog signaling pathway XREF_BIBR; acts as an molecular assembler of an E3 ubiquitin ligase complex, which plays a crucial role in regulating normal mitotic progression XREF_BIBR; and functions in the DNA damage signaling pathway by phosphorylating p53 thereby initiating a p53 apoptotic response XREF_BIBR."
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"44 However, massive expansion of the many copies of TP53 identified in elephants was suggested to increase cellular sensitivity to DNA damage by triggering p53-dependent apoptosis, which leads to efficient removal of mutant cells.14Previous studies have also shown that many genes related to cancer control (including DNA damage and repair, immune response, and tumor suppression) evolved under positive selection, duplication, and amino acid changes in several long-lived lineages, suggesting that they share a mechanism."
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"We considered two main possible mechanisms : p53 binding might be enhanched by the increase in p53 levels due to cooperative binding, or p53 PTMs and in particular p53-CTD acetylation might render p53 binding to REs more stable, since we measured p53 acetylation levels at Lysine 382 that correlate well with the observed modulation in p53 binding kinetics (more stable 2h post IR than in basal conditions and 4h post IR)."
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"To further confirm the contribution of the p85alpha dependent p53-p300 interaction and p53 acetylation (Lys370) to UVB induced p53 transactivation, we next analyzed the recruitment of p300 and p53 to the p53 responsive element (p53-RE) within the promoter region of p53 target genes in response to UVB irradiation in the presence or absence of p85alpha expression."
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"Homeodomain interacting protein kinase-2 (HIPK2) is an important regulator of p53 apoptotic function, thus we have previously shown that HIPK2 phosphorylates p53 at serine 46 (Ser46) after severe DNA damage, inducing p53 specific apoptotic transcriptional activity XREF_BIBR - XREF_BIBR."
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"We show that the C-terminal sequence of PEPD binds to the PRD in p53, which allows PEPD to accomplish two important tasks : (1) to prevent nuclear p53 phosphorylation in its transactivation domain andto reduce free nuclear p53 level, leading to inhibition of p53 trans-activation and trans-suppression activities, and (2) to prevent mitochondrial translocation of nuclear and cytosolic p53 by preventing p53 from binding to MDM2 (Figs."
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"As a methyltransferase, SET8 methylates lysine 382 of p53 to modulates p53 activity so as to change its transcriptional activity for downstream targets, furthermore, SET8 knockdown has been shown to upregulate cells ' sensitivity to cell death and cell cycle arrest following DNA damage by suppressing the biological function of p53 XREF_BIBR."
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"Cells pretreated with nutlin-3 to stabilize p53 levels showed a dose dependent increase in p53 acetylation after TV6 treatment, with minimal change in total p53 levels, indicating that increased p53 acetylation was independent of increase in total p53 (XREF_FIG and XREF_SUPPLEMENTARY)."
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"These data suggest that p68, p53 and Delta133p53alpha may form part of a complex feedback mechanism to regulate the expression of Delta133p53, with consequent modification of p53 mediated transcription, and may modulate the function of p53 in breast and other cancers that harbour wild type p53."
eidos
"However , herein we demonstrate that TP53 induces TPRKB degradation in a concentration-dependent manner that can be alleviated either through PRPK expression or proteosomal inhibition ( Fig 7A ) , providing a potential mechanism for TPRKB dependency only in the presence of TP53 alterations ( Fig 7B ) ."
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"Inhibition of p53 ubiquitination by DNA damage not only prevents p53 from degradation but also promotes its nuclear accumulation leading to transactivation of a number of downstream genes that are essential for the control of cell cycle progression, cell survival, and cellular senescence."
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"Employing SKH-1 hairless mice that were p53 sufficient (WT) or deficient (p53+/−), our findings demonstrated that p53 is an essential mediator of NM-induced apoptosis in mouse skin, and that p53 deficiency/decreased p53 activation significantly reduces early apoptotic cell death and neutrophilic infiltration induced by NM."
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"This special issue compiles emerging non canonical functions and regulation of p53, including (1) novel mechanisms regulating the expression and activities of p53 and its family members, p63 and p73; (2) p53 proteoforms and binding potential of p53 to local DNA structures; (3) novel oncogenic pathways and stemness regulated by p53; (4) roles of p53 in non canonical cell death; (5) roles of p53 in glucose, lipid, and nucleotide metabolism, and (6) roles of p53 in immunity."
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"For example, MDM2 can directly bind to p53 to inhibit its transcriptional activity; quickly enhance the ubiquitination and degradation of p53 through ubiquitin-E3 ligase; and promote p53 degradation by blocking p53 's transport from the nucleus to the cytoplasm XREF_BIBR XREF_BIBR."
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"The phosphorylation of p53 on Ser15 was demonstrated to prevent p53 negative regulator MDM2 binding and to result in the accumulation and increased transcriptional activation ability of p53.35 These results indicated that aforementioned apoptotic response was induced by a p53 dependent endogenous apoptosis pathway."
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"Indeed, phosphorylation of p53 activates the release of cytochrome c and caspase-9 via target genes such as Bax (BCL-2 [B-cell lymphoma-2] associated protein), Bak (BCL-2 homologous antagonist and killer), Noxa (damage), and PUMA (p53 upregulated modulator of apoptosis) [XREF_BIBR]."
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"Induction of DNA damage initiates a cascade of signalling with p53 activation (phosphorylation at Ser 15 and Ser 20) and subsequent transcriptional activation of p53 response genes (including p21, GADD45, BAX, PUMA, Bcl2 and NOXA), thus provoking cell cycle arrest and/or apoptosis [ xref ]."
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"GADD45 stabilizes phosphorylation of serine 15 of p53 providing a positive feedback signal in activation of the p53 pathway, Plk3 phosphorylates p53 on serine 20 and enhances p53 stabilization, and p53 dependent activation of Plk2 prevents mitotic catastrophe after spindle damage."
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"These studies (mostly performed in other, mainly immunological contexts) frequently show (similar to virus infections) : (a) interactions with components of the PI3K and Akt signaling pathway as well as inhibition or promotion of phosphoinositide synthesis, (b) reduced p53 gene expression, inhibition of the activity of p53 protein, or induction of p53 degradation, and (c) activation of HIF-1 (mainly by stabilization of HIF-1alpha) (XREF_FIG)."
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"These data demonstrate that wild-type p53 over-expression can both positively and negatively regulate life span independent of foxo, while at the same time they suggest that foxo acts in males to modulate (reverse) the tissue specific pattern of p53 life span effects, thereby producing sexually antagonistic effects of p53."
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"Since p53 phosphorylation at Ser15 has been shown to increase p53 stability and enhance its transcriptional activity XREF_BIBR, XREF_BIBR, our observations suggest that the higher p21 protein level in the Bat3-KD cells is unlikely to be due to increased p53 transcriptional activity."
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"Analysis of p53 chromatin immunoprecipitation sequencing (ChIP-seq) experiments performed in HCT116 cells XREF_BIBR indicates the presence of a significant peak of p53 interaction in two independent experiments involving p53 activation induced by Nutlin3 or 5 ' fluorouracil (5FU)), at the same position, approximately 800 bp away from the GAS5 transcriptional start site (TSS), indicating that p53 directly controls GAS5 transcription."
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"P53 plays a pivotal role for senescence induction; the DNA damage response activates ataxia telangiectasia (ATM) and Rad3-related (ATR) kinases, which in turn activate the p53/p21 axis by phosphorylation of both p53 and its ubiquitin ligase Mdm2, leading to the stabilization of p53 levels [51]."
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"Simple readouts for p53 activation under nucleolar stress conditions are an increased p53 protein levels (stabilization or accumulation following blockage of ubiquitin-proteasomal degradation), reduced p53 binding to MDM2/HDM2, increased p53 mRNA levels under a long-lasting stress, elevated mRNA levels of p53 target genes, typically CDKN1A (p21) and BAX, and corresponding cell phenotypes such as cell cycle arrest, autophagy, DNA repair, senescence, or apoptosis 89."
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"71 Recently a novel function of IAV NC in inducing host cell death was also identified via a yeast two-hybrid screen, the researchers identified RING finger protein 43, a RING-type E3 ubiquitin ligase, as a novel interactor of NC and as an important partner of NC to modulate p53 ubiquitination levels, which causes p53 stabilization and enhances apoptosis level in IAV-infected cells."
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"Biochemical analysis suggests that the brain abnormalities in p53-KQ mice are in part due to activation of p53 target genes and subsequent induction of apoptosis compared to the wild-type mice, demonstrating that mimicking acetylation of p53 C-terminus leads to elevated p53 transcriptional activities."
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"The intimate addiction of cancer cells to the sustained activity of E6 represents an advantage for the development of anti-cancer drugs, since perturbing E6 activities can restore the intracellular levels of active p53 and reactivate p53 mediated pathways, leading to oncogene induced senescence and eventually apoptosis of cancer cells 20."
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"It has been shown by DNA binding, transcriptional activation and tumor suppressing assays that the incorporation of a second mutation into oncogenic p53, referred to as second-site suppressor mutation, can rescue the normal activity of p53 as described later in the text for the current hot spot mutations."
eidos
"Notably , over 70 % of osteosarcoma has structural variants or mutations in the TP53 gene , Ewing sarcoma is rarely mutated for TP53 due to EWS-FLI1 's inhibitory effect on TP53 , non-uterine LMS has a high rate ( ~ 50 % ) of TP53 mutation , and well - and de-differentiated LPSs are defined by amplification of MDM2 ."
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"Here we report the first account of the dynamics of mutation induced structural transition of native p53 to an aberrant gain-of-function state, studying the wildtype (WT) and high incidence contact (R273C) and structural (R175H) mutant p53 (mutp53) through molecular dynamics simulation."
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"Taken together, these data demonstrate that inactivation of Sirt3 significantly enhances p53-mediated ferroptosis upon ROS stress and this upregulation, at least, in part contributes to p53-dependent tumor growth suppression.It is well accepted that Sirt1 plays an important role in regulating p53-mediated transcriptional activation by deacetylating p53 (Zhao et al., 2008)."
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"In cancer cells, NRF3 upregulates assembly of the 20S proteasome by directly inducing gene expression of the 20S proteasome maturation protein POMP Interestingly, NRF3 knockdown not only increases p53 and Rb protein levels but also increased p53 activities for tumor suppression, including cell-cycle arrest and induction of apoptosis."
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"Activated p53 (protein product of TP53) is a DNA-binding transcription factor that targets different proteins that are either involved in apoptosis (e.g., Bad, Bax, Puma, Fas, Apaf1, Noxa) or can induce cell cycle arrest (e.g., BTG2, CDNK1/p21/pRb/E2F1 pathway, GADD45) and activate DNA repair mechanisms (e.g., p48, XPC, PCNA, DDB2) after exposure to UV light, ionizing radiation or other DNA-damaging agents [17]."
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"HBeAg and its precursors could disrupt p53-NUMB and HDM2-NUMB interactions and tricomplex p53-HDM2-NUMB formation, inhibit the acetylation and translocation of p53 from cytosol to the nucleus, promote HDM2 mediated ubiquitination and degradation of p53, and suppress p53 dependent apoptosis."
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"In the latter cell line (see the quantitation of protein bands in XREF_FIG), along with the solid tumor cell lines, the expression of p53 did not increase on stimulation with BM-H, thus confirming the p21 dependent, p53 independent mechanism of BM-H extract on all tested cell lines."
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"To evaluate whether the p53 pathway was activated in these PIM1 containing prostate cancer cells, we carried out quantitative reverse transcriptase-PCR (qRT-PCR) analysis of mRNA from cells expressing PIM1 at early and late passages (XREF_FIG), and examined the levels of three p53 activated genes, p53 inducible nuclear protein 1, DNA-damage inducible transcript 4, and p21."
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"We found that although the total p53 protein level was not changed significantly, the nuclear p53 protein level was progressively reduced, and correspondingly, the cytoplasmic level of p53 progressively increased, suggesting an increase in p53 nuclear to cytoplasmic translocation after 4-12 h of LPS stimulation (XREF_FIG)."
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"It is unclear how H1.2 translocation to the cytoplasm is stimulated, but phosphorylation of its T146 residue (H1.2T146-P) together with p300-mediated acetylation of p53 has been shown to block p53-H1.2 binding, allowing p53 to activate transcription of its target genes such as BAX and thereby promote cell death (Kim et al. 2012)."
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"P53 is well‐recognized to play a key role in cell‐cycle control, DNA repair and cellular stress responses, and recent studies has reported that p53 activation of p53 can regulate apoptosis, cellular senescence and organismal ageing. xref SA‐β‐gal is an extensively utilized marker for cell senescence, and the β‐galactosidase activity can be detected at pH 6.0 in replicative or induced senescence cells but undetectable from proliferating cells. xref Levels of p53 often gradually increase during the process of replicative senescence, whereas the presence of SA‐β‐gal marker can distinguish senescent cells during cell passages independent of DNA synthesis. xref Thus, a time‐lag may exist between the time‐point of increased p53 levels and the presence of SA‐β‐gal activity."
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"The regulation of p53 stability and activity involves many proteins, such as the antagonist MDM2 that binds the transactivation domain and also targets p53 for ubiquitination and degradation, or the kinases DNA-PK and ATM that phosphorylate p53 at several of its many sites for post-translational modification [XREF_BIBR, XREF_BIBR]."
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"Taken together, these results demonstrate that down-regulation of p53 expression or inhibition of p53-dependent gene transcription enhanced chemoresistance to CDDP in MCF-7 and MCF-7 cells under both treatments, suggesting a key role of p53 in overcoming the chemoresistance of MCF-7 cells."
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"Using mass spectrometry to identify nuclear and cytoplasmic CBP interacting proteins that regulate compartmentalized CBP E4 activity, we identified deleted in breast cancer 1 (DBC1) as a stoichiometric CBP interacting protein that negatively regulates CBP dependent p53 polyubiquitination, stabilizes p53, and augments p53 dependent apoptosis."
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"Summary of programmed cell deaths in stem cell-based therapyPart I during the intrinsic pathway: During the intrinsic pathways, DNA damage, as a significant inducer, can stabilize and activate p53 by phosphorylation (for example, the phosphorylation of p53 at Ser46 can induce the p53-dependent apoptotic pathway caused by DNA damage[137]), leading to p53 nuclear translocation[119]."
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"However, p53 phosphorylation by specific kinases, e.g., p38, following osmotic cell shrinkage, or ATM (ataxia-telangiectasia-mutated kinase)/ATR (ataxia-telangiectasia and Rad3 related) following cisplatin induced DNA damage stabilizes p53 and hence ensures apoptosis and depresses cell proliferation."
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"Here, using yeast, we show that transient p53 overexpression induced the formation of p53 prion aggregates that were transmitted for> 100 generations, found in lysate pellets, stained with Thioflavin T, and transmitted by cytoplasmic transfer, or transfection with lysates of cells carrying the prion or with p53 amyloid peptide."
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"Over-expression of hepatic p53 and p63 was achieved by tail vein injection of adenoviral vectors activating p53 (SignaGen Laboratories, USA, ref # SL100,777), p63 (SignaGen Laboratories, USA, ref # 189SL100,865) and GFP (SignaGen Laboratories, USA, ref # SL100,833) (1 x 10 9 VGml -1)."
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"However, ribosomal stress induced by actinomycin D treatment specifically leads to p300/CBP-mediated acetylation of both p53 and Hdm2, which in turn upregulates p53 transcriptional activity and inhibits Hdm2 E3 ubiquitin ligase activity (Carter and Vousden, 2009, Lee and Gu, 2010)."
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"N-acetyl cysteine (NAC), superoxide dismutase, and catalase mimetic attenuate UVB induced p53 stabilization without altering the transcriptional activation and cell cycle arrest functions of p53, suggesting a role for oxidative stress in UVB induced p53 stabilization and accumulation."
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"The outcome of p53 activation may depend on the cell type, amount of DNA damage, levels of p53 induced, different p53 post-translational modifications, recruitment of different co-factors to p53, and transcriptional activation of different sets of p53 target genes [XREF_BIBR, XREF_BIBR]."
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"Knockdown of individual subunits of CK2 demonstrated a differential decrease of gene expression of not only NF-kappaB but also cell survival (BCL-XL) and cell cycle progression (CCND1) genes, whereas an increase of TP53 family genes known to promote growth arrest and apoptosis (p53 and Tap63) was observed."
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"Similarly, we found that RGS6 is required for urothelial BBN induced p53 activation and caspase 3 cleavage as the transient peak in p53 activation (phosphorylation of S15) and in caspase 3 cleavage in RGS6 +/+ mice at 2-3 days following BBN exposure was significantly blunted in RGS6 -/- mice."
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"Unfortunately, it does not lead to any conclusions concerning prospective molecular drug targets.Among the parameters of the p53 signaling module, many are particularly important, including those directly affecting the level of p53 protein (synthesis of p53 mRNA, p53 transcript degradation, p53 translation rate) and its inhibitor, Mdm2 (synthesis of Mdm2 mRNA, Mdm2 transcript degradation, Mdm2 translation rate, Mdm2p protein spontaneous degradation, Mdm2 degradation by Chk2)."
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"Increased levels of p53 upregulate the downstream molecules p21 (XREF_FIG and XREF_FIG) and p27 in p53 wt and, at least some, p53 mut cancer cells, downregulating FoxM1, and leading to inhibition of cell cycle at G 2 -M. Currently, small molecules designed to inhibit HDM2 mediated ubiquitination are apparently only being tested in patients with p53 wt tumours."
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"Furthermore, targeting p53 null cells requires a different approach altogether, which can be based on the identification of synthetic lethality (increased sensitivity to inhibition of another pathway in the absence of p53) or induction of a p53 like response by the activation of the p53 family member s p73 or p63 [XREF_BIBR]."