Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The CDC25B phosphatase regulates the activation of CDK1-Cyclin B at the onset of mitosis, being a key target of the checkpoint pathways activated by cellular stress and DNA damage. Previous work has reported that checkpoint activation induces the sequestration of CDC25B in the cytoplasm. Here we show that in response to UV irradiation, the levels of CDC25B protein can be downregulated independently of classical checkpoints pathways such as p53, ATM/ATR and p38 MAPK. We also show that translational repression mediated by eIF2alpha phosphorylation regulates CDC25B expression levels. Taken together, our results illustrate a new mechanism of CDC25B regulation in response to stress.
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PMID:UV-induced downregulation of the CDC25B protein in human cells. 2017 18

Epidemiological studies suggest that human papillomavirus (HPV)-infected women who smoke face an increased risk for developing cervical cancer. We have previously reported that exposure of HPV-positive organotypic cultures to benzo[a]pyrene (BaP), a major carcinogen in cigarette smoke, resulted in enhanced viral titers. Since BaP is known to deregulate multiple pathways of cellular proliferation, enhanced virion synthesis could result from carcinogen/host cell interaction. Here, we report that BaP-mediated upregulation of virus synthesis is correlated to an altered balance between cell cycle-specific cyclin-dependent kinase (CDK) activity profile compared with controls. Specifically, BaP treatment increased accumulation of hyperphosphorylated retinoblastoma protein (pRb) which coincided with increased cdc2/CDK1 kinase activity, but which further conflicted with the simultaneous upregulation of CDK inhibitors p16(INK4) and p27(KIP1), which normally mediate pRb hypophosphorylation. In contrast, p21(WAF1) and p53 levels remained unchanged. Under these conditions, CDK6 and CDK2 kinase activities were decreased, whereas CDK4 kinase activity remained unchanged. The addition of purvalanol A, a specific inhibitor of CDK1 kinase, to BaP-treated cultures, resulted in the production of noninfectious HPV type 31b (HPV31b) particles. In contrast, infectivity of control virus was unaffected by purvalanol A treatment. BaP targeting of CDK1 occurred independently of HPV status, since BaP treatment also increased CDK1 activity in tissues derived from primary keratinocytes. Our data indicate that HPV31b virions synthesized in the presence of BaP were dependent on BaP-mediated alteration in CDK1 kinase activity for maintaining their infectivity.
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PMID:Downregulation of Cdc2/CDK1 kinase activity induces the synthesis of noninfectious human papillomavirus type 31b virions in organotypic tissues exposed to benzo[a]pyrene. 2018 98

Zinc is an essential nutrient for humans; however, this study demonstrated for the first time that an elevated zinc status, created by culturing cells at optimal plasma zinc concentration attainable by oral zinc supplementation, is cytotoxic for normal human bronchial epithelial (NHBE) cells. p53 plays a central role in the modulation of cell signal transduction in response to the stress from DNA damage, hypoxia and oncogene activation. The present study was designed to determine whether the previously reported increased Gadd45 expression and delayed G2/M cell cycle progression in zinc-supplemented NHBE cells is p53-dependent, and to decipher the mechanisms responsible for the regulation of Gadd45 expressions by p53, and elucidate the Gadd45 functions in impaired cell growth and cell cycle progression in NHBE cells. Cells were cultured for one passage in different concentrations of zinc: <0.4 micromol/L (ZD) as severe zinc-deficient; 4 micromol/L (ZN) as normal zinc level in culture medium; 16 micromol/L (ZA) as normal human plasma zinc level; and 32 micromol/L (ZS) as the high end of plasma zinc attainable by oral supplementation. Inhibition of cell growth and upregulation of p53 mRNA and protein expression were observed in ZS cells. Most importantly, ZS treatment also enhanced Gadd45 nuclear protein level and promoter activity, decreased CDK1-Cyclin B1 level and delayed G2/M cell cycle progression. These changes were normalized to those observed in ZN by treating ZS cells with Pifitherin, an inhibitor of p53 transactivation activity. Thus, our findings support the p53 dependency of the Gadd45-CDK1/Cyclin B1-G2/M cell cycle progression pathway in ZS NHBE cells.
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PMID:Enhanced Gadd45 expression and delayed G2/M progression are p53-dependent in zinc-supplemented human bronchial epithelial cells. 2066 93

The p16(INK4a) protein is considered to regulate the cell cycle progression mainly by inhibiting cyclin-dependent kinases (CDKs) 4 and 6 activity and leading to an arrest in G(0)/G(1). Here, we report that ectopic expression of p16(INK4a) in three p16-/pRb(Wt)/p53(Wt) human cancer cell lines MCF7, U2OS and U87 induces S-phase lengthening along with G(1) accumulation. S-phase lengthening is suggested by the discrepancy between the unchanged or even increased percentage of cells in S phase found by flow cytometry DNA content analysis and the drop of BrdU labelling, and demonstrated by IdU/BrdU double labelling. p16(INK4a) induces a profound decrease in the CDK4/6-mediated pRb phosphorylation on Ser-807/811, a downregulation of CDK2 and CDK1 protein expression independently of G(1) accumulation, and a decrease in Thr/Pro phosphorylation in part carried out by CDKs. In MCF7 cells, overexpression of the p16 G101W mutant, which is unable to inhibit CDK4/6 kinase activity and shows a modified subcellular localization, does not provoke the S-phase lengthening and the inhibition of Ser807/811-pRB and of Thr/Pro phosphorylation as wild-type p16(INK4a) does. Our results demonstrate that p16(INK4a) induces a S-phase lengthening independently of cellular origin. The CDK4/6 kinase activity inhibition together with the reduced expression of CDK2 and CDK1 acting downstream of G(1) phase may prevent cells from any possible kinasic compensatory mechanisms, and thus lead to a cell cycle progression inhibition.
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PMID:S-phase lengthening induced by p16(INK4a) overexpression in malignant cells with wild-type pRb and p53. 2081 32

p21(Waf1/Cip1) is a p53 transcription target implicated in both major functions of the tumor suppressor--cell cycle arrest and apoptosis. It is a potent inhibitor of the key cyclin-dependent kinases (CDK1-4), and has been thought to be the main mediator of p53-dependent G1 and G2 arrest. However, an increasing body of information suggests that in addition to its cell-cycle inhibitory activity, p21 can affect p53-dependent apoptosis. These data have been obtained from experiments in which p53 is activated primarily by genotoxic stress. In this study, we use the selective MDM2 antagonist, nutlin-3a, as a nongenotoxic p53 activator and show that the cell-cycle arrest function of p21 is dependent on the cellular context. In most cancer cell lines, p53-dependent p21 induction is essential for cell-cycle arrest, but in some, p21 is dispensable. Depletion of p21 did not increase the apoptotic response to nutlin-3a in all seven cancer cell lines tested and p21 overexpression did not protect apoptosis-sensitive lines from death. p21 was found to mediate nutlin-induced p53-dependent downregulation of another antiapoptotic protein, survivin, without significantly affecting the apoptotic outcome. Taken together our results suggest that p21 induction does not affect the apoptotic response to nongenotoxic p53 activation.
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PMID:p21 does not protect cancer cells from apoptosis induced by nongenotoxic p53 activation. 2087 30

We recently established that NCPMF-60, a newly synthesized flavonoid, is an active cytotoxic component. The molecular mechanisms by which NCPMF-60 exerts its cytotoxic activity are currently unknown. In this study, we show that NCPMF-60 induces G2/M phase arrest and apoptosis in human hepatocellular carcinoma HepG2 cells. After treatment of HepG2 cells with NCPMF-60, cell cycle-related proteins, such as cyclin B1, cyclin H, CDK7, and p-CDK1 (Thr161), were downregulated, whereas p21 and p-CDK1 (Thr14/Tyr15) were upregulated. The activity of CDK1/cyclinB complex was also inhibited by NCPMF-60. In addition, we observed poly(ADP-ribose) polymerase cleavage and activation of caspase 3 and caspase 9. The expression ratio of Bax/Bcl-2 was increased in the treated cells, in which Bax was also upregulated. We also found that the expression of p53 and its phosphorylation at Ser15 accumulated after the treatment of NCPMF-60. Moreover, upregulation of p21, p53-upregulated modifier of apoptosis, and Bax, three p53-target gene products, and the downregulation of Bcl-2 and MDM2, were observed in NCPMF-60-treated cells. However, p53 is not the only regulator in the stimulation of NCPMF-60 on p21 transcriptional level and posttranscriptional level. These results suggested that NCPMF-60 indeed activated the p53 pathway, which may contribute to its induction of cell cycle arrest and apoptosis in HepG2 cells. Collectively, our findings show that cell cycle arrest and apoptosis induced by NCPMF-60 was associated with the activation of p53 pathway and the inhibition of CDK-activating kinase activity in HepG2 cells.
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PMID:NCPMF-60 induces G2/M cell cycle arrest and apoptosis in human hepatocellular carcinoma HepG2 cells. 2094 30

The p16(INK4a) protein regulates cell cycle progression mainly by inhibiting the activity of G1-phase cyclin-dependent kinases (CDKs) 4 and 6, the subsequent retinoblastoma protein (pRb) phosphorylation and E2F transcription factor release. The p16(INK4a) protein can also repress the activity of other transcription factors, such as c-myc, nuclear factor-kappaB and c-Jun/AP1. Here, we report that, in two p16(-/-), pRb(WT) and p53(WT) cell lines (MCF7 and U87), p16(INK4a) overexpression induces a dramatic decrease in CDK1 protein expression. In response to p16(INK4a), the decreased rate of CDK1 protein synthesis, its unchanged protein half-life, unreduced CDK1 mRNA steady-state levels and mRNA half-life allow us to hypothesize that p16(INK4a) could regulate CDK1 expression at the post-transcriptional level. This CDK1 downregulation is mediated by the 3'-untranslated region (3'UTR) of CDK1 mRNA as shown by translational inhibition in luciferase assays and is associated with a modified expression balance of microRNAs (miRNAs) that potentially regulate CDK1, analyzed by TaqMan Human microRNA Array. The p16(INK4a)-induced expression of two miRNAs (miR-410 and miR-650 chosen as an example) in MCF7 cells is confirmed by individual reverse transcription-qPCR. Furthermore, we show the interaction of miR-410 or miR-650 with CDK1-3'UTR by luciferase assays. Endogenous CDK1 expression decreases upon both miRNA overexpression and increases with their simultaneous inhibition. The induction of miR-410, but not miR-650 could be related to the pRb/E2F pathway. These results demonstrate the post-transcriptional inhibition of CDK1 by p16(INK4a). We suggest that p16(INK4a) may regulate gene expression by modifying the functional equilibrium of transcription factors and consequently the expression balance of miRNAs.
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PMID:Cyclin-dependent kinase 1 expression is inhibited by p16(INK4a) at the post-transcriptional level through the microRNA pathway. 2117 85

UHRF1 [ubiquitin-like protein, containing PHD (plant homeodomain) and RING finger domains 1] is required for cell cycle progression and epigenetic regulation. In the present study, we show that depleting cancer cells of UHRF1 causes activation of the DNA damage response pathway, cell cycle arrest in G2/M-phase and apoptosis dependent on caspase 8. The DNA damage response in cells depleted of UHRF1 is illustrated by: phosphorylation of histone H2AX on Ser139, phosphorylation of CHK (checkpoint kinase) 2 on Thr68, phosphorylation of CDC25 (cell division control 25) on Ser216 and phosphorylation of CDK1 (cyclin-dependent kinase 1) on Tyr15. Moreover, we find that UHRF1 accumulates at sites of DNA damage suggesting that the cell cycle block in UHRF1-depleted cells is due to an important role in damage repair. The consequence of UHRF1 depletion is apoptosis; cells undergo activation of caspases 8 and 3, and depletion of caspase 8 prevents cell death induced by UHRF1 knockdown. Interestingly, the cell cycle block and apoptosis occurs in p53-containing and -deficient cells. From the present study we conclude that UHRF1 links epigenetic regulation with DNA replication.
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PMID:UHRF1 depletion causes a G2/M arrest, activation of DNA damage response and apoptosis. 2121 17

Cdc25B phosphatases function as key players in G2/M cell cycle progression by activating the CDK1-cyclinB1 complexes. They also have an essential role in recovery from the G2/M checkpoint activated in response to DNA damage. Overexpression of Cdc25B results in bypass of the G2/M checkpoint and illegitimate entry into mitosis, and also causes replicative stress, leading to genomic instability. Thus, fine-tuning of Cdc25B expression level is critical for correct cell cycle progression and G2 checkpoint recovery. However, the transcriptional regulation of Cdc25B remains largely unknown. Earlier studies have shown that the tumor suppressor p53 overexpression transcriptionally represses Cdc25B; however, the molecular mechanism of this repression has not yet been elucidated, although it was suggested to occur through the induction of p21. Here we show that Cdc25B is downregulated by the basal level of p53 in multiple cell types. This downregulation also occurs in p21-/- cell lines, indicating that p21 is not required for p53-mediated regulation of Cdc25B. Deletion and mutation analyses of the Cdc25B promoter revealed that downregulation by p53 is dependent on the presence of functional Sp1/Sp3 and NF-Y binding sites. Furthermore, chromatin immunoprecipitation analyses show that p53 binds to the Cdc25B promoter and mediates transcriptional attenuation through the Sp1 and NF-Y transcription factors. Our results suggest that the inability to downregulate Cdc25B after loss of p53 might contribute to tumorigenesis.
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PMID:Cdc25B is negatively regulated by p53 through Sp1 and NF-Y transcription factors. 2124 64

Triazoloacridone C-1305, a new topoisomerase II inhibitor, exhibits potent cytostatic activity toward various tumours under in vitro and in vivo conditions. Interestingly, mouse cells lacking poly(ADP-ribose) polymerase-1 are much more sensitive to C-1305 than their normal counterparts. In the present study we tested the hypothesis that the functional status of p53 in tumour cells might have an impact on the efficiency of C-1305 in experiments with both p53-deficient human HL-60 promyelocytic leukemia cells and human MCF-7 breast cancer cells harboring a functional p53 pathway. Exposure of both cancer cell lines to C-1305 reduced the number of viable cells in a time- and concentration-dependent manner. Remarkably, however, HL-60 cells were much more strongly affected than MCF-7 cells. Measurements of DNA concentrations in single cells revealed that C-1305 arrested the tested cancer cells at the G/M transition. Analysis of the cell cycle and apoptosis regulators revealed that C-1305 strongly elevated phosphorylation of CDK1 at the inhibitory sites (Thr14/Tyr15) in HL-60 cells. Furthermore, C-1305 increased phosphorylation of pRb protein and CDK2 at Thr160 in HL60 cells, but not in MCF-7 cells. These observations suggest that C-1305 abrogates the restriction checkpoint and promotes G1/S transition in cells lacking functional p53.
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PMID:Triazoloacridone C-1305 abrogates the restriction checkpoint in cells lacking functional p53 and promotes their accumulation in the G2/M phase of the cell cycle. 2127 61


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