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 biological activity of retinoic acid (RA) was examined in human hepatoma Hep3B cells. Under serum-deprived conditions, RA induced S/M-phase elevation and mitotic index increase within 24 h, followed by apoptosis. This RA-induced apoptosis was accompanied by p53-independent up-regulation of endogenous p21(CIPI/Waf1) and Bax proteins, as well as activation of p34(cdc2) kinase, and increase of Rb2 protein level and phosphorylation pattern. In addition, RA had no effect on the levels of Bcl-XL; Bcl-XS; cyclins A, B, D1, D3, or E; or Rb1 expression but markedly down-modulated Cdk2 kinase activity and reduced Cdk4 expression. RA also slightly delayed p27(Kip1) expression. Olomoucine, a potent p34(cdc2) and Cdk2 inhibitor, effectively blocked RA-mediated p34(cdc2) kinase activation and prevented RA-induced apoptosis. Furthermore, antisense oligonucleotide complementary to p21(CIP2/Waf1) and p34(cdc2) mRNA significantly rescued RA-induced apoptosis. Our data indicate that p21(CIP2/Waf1) overexpression may not be the only regulatory factor necessary for RA-induced apoptosis in human hepatoma Hep3B cells. RA treatment leads to Rb2 hyperphosphorylation, and p34(cdc2) kinase activation is coincident with an aberrant mitotic progression, followed by appearance of abnormal nucleus. This aberrant cell cycle progression appeared requisite for RA-induced cell death. These findings suggest that inappropriate regulation of the cell cycle regulators p21(CIP2/Waf1) and p34(cdc2) is coupled with induction of Bax and involved in cell death with apoptosis when Hep3B cells are exposed to RA.
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PMID:Induction of p21(CIP1/Waf1) and activation of p34(cdc2) involved in retinoic acid-induced apoptosis in human hepatoma Hep3B cells. 1009 16

G1/S and G2/M cell cycle checkpoints maintain genomic stability in eukaryotes in response to genotoxic stress. We report here both genetic and functional evidence of a Gadd45-mediated G2/M checkpoint in human and murine cells. Increased expression of Gadd45 via microinjection of an expression vector into primary human fibroblasts arrests the cells at the G2/M boundary with a phenotype of MPM2 immunopositivity, 4n DNA content and, in 15% of the cells, centrosome separation. The Gadd45-mediated G2/M arrest depends on wild-type p53, because no arrest was observed either in p53-null Li-Fraumeni fibroblasts or in normal fibroblasts coexpressed with p53 mutants. Increased expression of cyclin B1 and Cdc25C inhibited the Gadd45-mediated G2/M arrest in human fibroblasts, indicating that the mechanism of Gadd45-mediated G2/M checkpoint is at least in part through modulation of the activity of the G2-specific kinase, cyclin B1/p34(cdc2). Genetic and physiological evidence of a Gadd45-mediated G2/M checkpoint was obtained by using GADD45-deficient human or murine cells. Human cells with endogenous Gadd45 expression reduced by antisense GADD45 expression have an impaired G2/M checkpoint after exposure to either ultraviolet radiation or methyl methanesulfonate but are still able to undergo G2 arrest after ionizing radiation. Lymphocytes from gadd45-knockout mice (gadd45 -/-) also retained a G2/M checkpoint initiated by ionizing radiation and failed to arrest at G2/M after exposure to ultraviolet radiation. Therefore, the mammalian genome is protected by a multiplicity of G2/M checkpoints in response to specific types of DNA damage.
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PMID:GADD45 induction of a G2/M cell cycle checkpoint. 1009 1

Cells of the TP53-deficient human leukemia cell line HL60 continue to progress throughout the cell cycle and arrest in the G2/M phase during protracted exposure to exponentially decreasing low-dose-rate radiation. We have hypothesized that G2/M-phase arrest contributes to the extent of radiation-induced cell death by apoptosis as well as to overall cell killing. To test this hypothesis, we used caffeine and nocodazole to alter the duration of G2/M-phase arrest of HL60 cells exposed to exponentially decreasing low-dose-rate irradiation and measured the activity of G2/M-phase checkpoint proteins, redistribution of cells in the phases of the cell cycle, cell death by apoptosis, and overall survival after irradiation. The results from these experiments demonstrate that concomitant exposure of HL60 cells to caffeine (2 mM) during irradiation inhibited radiation-induced tyrosine 15 phosphorylation of the G2/M-phase transition checkpoint protein CDC2/p34 kinase and reduced G2/M-phase arrest by 40-46% compared to cells irradiated without caffeine. Radiation-induced apoptosis also decreased by 36-50% in cells treated with caffeine and radiation compared to cells treated with radiation alone. Radiation survival was significantly increased by exposure to caffeine. In contrast, prolongation of G2/M-phase arrest by pre-incubation with nocodazole enhanced radiation-induced apoptosis and overall radiation-induced cell killing. To further study the role of cell death by apoptosis in the response to exponentially decreasing low-dose-rate irradiation, HL60 cells were transfected with the BCL2 proto-oncogene. The extent of G2/M-phase arrest was similar for parental, neomycin-transfected control and BCL2-transfected cells during and after exponentially decreasing low-dose-rate irradiation. However, there were significant differences (P < 0.01) in the extent of radiation-induced apoptosis of parental and neomycin- and BCL2-transfected cells after irradiation, with significantly less radiation-induced apoptosis and higher overall survival in BCL2-transfected cells than similarly irradiated control cells. These data demonstrate that radiation-induced G2/M-phase arrest and subsequent induction of apoptosis play an important role in the response of HL60 cells to low-dose-rate irradiation and suggest that it may be possible to increase radiation-induced apoptosis by altering the extent of G2/M-phase arrest. These findings are clinically relevant and suggest a novel therapeutic strategy for increasing the efficacy of brachytherapy and radioimmunotherapy.
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PMID:G2/M-phase arrest and death by apoptosis of HL60 cells irradiated with exponentially decreasing low-dose-rate gamma radiation. 1036 Jul 85

A novel synthetic retinoid, 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid (CD437), is a selective ligand of the RARgamma nuclear receptor. We examined the in vitro effects of CD437 and found that CD437 induces S phase arrest within 24 to 48 h, followed by cell death, in the p53-negative Hep3B and the p53-positive HepG2 human hepatoma cell lines. Based on observations of cellular and nuclear fragmentation, chromatin condensation, and DNA fragmentation, the CD437-mediated cell-killing effect appears to be due to apoptosis. On morphological examination, a number of CD437-treated cells were found to have increased 5- to 10-fold in size and persisted as single giant cells without cell division, while the remainder underwent nuclear division (multiple nuclei) but were unable to complete cytokinesis, and finally all died by apoptosis. In HepG2 cells that possessed wild-type p53, CD437-induced S phase arrest and apoptosis were accompanied by the up-regulation of cyclin A, cyclin B, p53, p21(CIP1/Waf1), Bad, and Bcl-Xs proteins and by a decrease in Bcl-2 protein levels. In Hep3B cells, CD437-mediated S phase arrest and apoptosis were also associated with a concomitant up-regulation of cyclin A, cyclin B, Bad, and Bcl-Xs. However, Hep3B cells did not express p53 or Bcl-2 messages. Olomoucine and roscovitine, the potent p34(cdc2) and CDK2 inhibitors, effectively blocked CD437-mediated cyclin A- and B-dependent kinase activation and prevented CD437-induced cell death. Furthermore, antisense oligonucleotide complementary to cyclin A and B mRNA significantly rescued CD437-induced apoptosis. These findings suggest that activation of cyclin A- and B-dependent kinases is a critical determinant of apoptotic death mediated by CD437.
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PMID:Involvement of cyclin-dependent kinase activities in CD437-induced apoptosis. 1052 23

The yeast Cdc14 phosphatase has been shown to play an important role in cell cycle regulation by dephosphorylating proteins phosphorylated by the cyclin-dependent kinase Cdc28/clb. We recently cloned two human orthologs of the yeast CDC14, termed hCDC14A and -B, the gene products of which share approximately 80% amino acid sequence identity within their N termini and phosphatase domains. Here we report that the hCdc14A and hCdc14B proteins interact with the tumor suppressor protein p53 both in vitro and in vivo. This interaction is dependent on the N termini of the hCdc14 proteins and the C terminus of p53. Furthermore, the hCdc14 phosphatases were found to dephosphorylate p53 specifically at the p34(Cdc2)/clb phosphorylation site (p53-phosphor-Ser(315)). Our findings that hCdc14 is a cyclin-dependent kinase substrate phosphatase suggest that it may play a role in cell cycle control in human cells. Furthermore, the identification of p53 as a substrate for hCdc14 indicates that hCdc14 may regulate the function of p53.
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PMID:The human Cdc14 phosphatases interact with and dephosphorylate the tumor suppressor protein p53. 1064 93

Curcumin (CCM), a major yellow pigment of turmeric obtained from powdered rhizomes of the plant Curcuma longa Linn, is commonly used as coloring agent in foods, drugs and cosmetics. In this study we report that gavage administration of 200 mg/kg or 600 mg/kg CCM effectively suppressed diethylnitrosamine (DEN)-induced liver inflammation and hyperplasia in rats, as evidenced by histopathological examination. Immunoblotting analysis showed that CCM strongly inhibited DEN-mediated the increased expression of oncogenic p21(ras) and p53 proteins in liver tissues of rats. In cell-cycle-related proteins, CCM selectively reduced the expression of proliferating cell nuclear antigen (PCNA), cyclin E and p34(cdc2), but not Cdk2 or cyclin D1. Moreover, CCM also inhibited the DEN-induced increase of transcriptional factor NF-kappa B. However, CCM failed to affect DEN-induced c-Jun and c-Fos expression. It has become widely recognized that the development of human hepatocellular carcinoma (HCC) is predominantly due to the chronic inflammation by virus, bacteria or chemical. Our results suggest a potential role for CCM in the prevention of HCC.
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PMID:Inhibition by curcumin of diethylnitrosamine-induced hepatic hyperplasia, inflammation, cellular gene products and cell-cycle-related proteins in rats. 1103 36

We previously found that p53 binds to the catalytic subunit of the p34(cdc2)/cyclin B1-kinase. In the present study we analyzed the functional consequences of this interaction. Binding of wild-type p53 to p34(cdc2)/cyclin B1 results in a significant decrease of its histone H1 kinase activity. Binding of p53 to the kinase is a prerequisite for the inhibition because a mutant p53 which lacks the binding region fails to influence the enzymatic activity. Furthermore, by using C-terminal fragments of p53 it became obvious that also some other structural elements in the N-terminal region are necessary for the inhibitory effect. Our present study provides evidence that p53 might regulate cell-cycle checkpoints not only on the transcriptional level but also by binding to the cell-cycle regulating kinase p34(cdc2).
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PMID:Downregulation of the cdc2/cyclin B protein kinase activity by binding of p53 to p34(cdc2). 1132 30

Loss of p53 function has been linked to increased responsiveness to taxane treatment of ovarian carcinoma in clinical studies. We recently reported that the acquisition of cisplatin resistance in an ovarian carcinoma cell line (IGROV-1) was associated with mutation of p53 and collateral sensitivity to paclitaxel. The increased sensitivity to paclitaxel of the cisplatin-resistant subline appeared to be pharmacologically relevant since it was reflected in an in vivo sensitization to taxanes. To investigate the cellular and molecular basis of this phenomenon, we performed a comparative study of cellular response to taxanes (paclitaxel and the novel analog IDN 5109) in the parental cell line, containing wild-type p53 and its cisplatin-resistant p53 mutant subline (IGROV-1/Pt1). IDN 5109 was included in this study because of its higher potency and efficacy compared with paclitaxel on both tumor systems. The pattern of cellular response of the two ovarian cell lines was different. In IGROV-1 cells, apoptosis was an early event consequent to a transient mitotic arrest. The cell death of IGROV-1/Pt1 cells was a somewhat slow and delayed event, following mitotic arrest and appearance of hyperploid cells. The increased cytotoxic effect of IDN 5109, compared with paclitaxel, was associated with more marked p34(cdc2) dephosphorylation in IGROV-1 cells and higher Bcl-2 phosphorylation in IGROV-1/Pt1 cells after 24 hr of treatment. In each cell line, these biochemical events were not correlated with parallel levels of mitotic cells. Attempts to reintroduce wild-type p53 in IGROV-1/Pt1 were unsuccessful. However, in other p53-deficient cells (osteosarcoma SAOS), taxane treatment was associated with hyperploid progression and the introduction of wild-type p53 resulted in a reduced sensivity. Although our approach does not allow definitive conclusions, these results suggest that loss of p53-dependent post-mitotic checkpoint results in a different time-course of taxane-induced cell death following DNA reduplication. These events, more evident after exposure to the potent analog IDN 5109, support the notion that the enhanced sensitivity of p53 mutant cells is closely related to the different mode of cell death.
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PMID:A role for loss of p53 function in sensitivity of ovarian carcinoma cells to taxanes. 1134 May 81

2-Methoxyestradiol (2-ME), an endogenous metabolite of 17beta-estradiol, is present in human blood and urine. Here we show for the first time that 2-ME significantly inhibited the growth of normal prostate epithelial cells and androgen-dependent LNCaP and androgen-independent DU145 prostate cancer cells. This growth inhibition was accompanied by a twofold increase in the G(2)/M population, with a concomitant decrease in the G(1) population, as shown by cell-cycle analysis. 2-ME treatment affected the cell-cycle progression of prostate cancer cells specifically by blocking cells in the G(2) phase. Immunoblot analysis of the key cell-cycle regulatory proteins in the G(2)/M phase showed a 14-fold increase in the expression of p21 and an eightfold increase in the expression of p34 cell division cycle 2 (cdc2). We also found an accumulation of phosphorylated cdc2 after 2-ME treatment. Furthermore, Wee 1 kinase was detectable after 2-ME treatment. 2-ME treatment also led to an increase in the activity of caspase-3, followed by apoptosis, as shown by terminal deoxynucleotidyl transferase-mediated deoxyuridine 5-triphosphate-biotin nick end-labeling and fluorescein isothiocyanate-poly(ADP-ribose) polymerase assay. Estrogen receptor levels did not change after treatment with 2-ME. Examination of the signaling pathways that mediate 2-ME-induced apoptosis showed reduction in the level of p53 expression and its DNA-binding activity. Given the fact that p53 mutations are common in patients with metastatic prostate cancer, our finding that 2-ME-mediated growth inhibition of human prostate cancer cells occurred in a p53-independent manner has considerable clinical significance. These findings, combined with the limited toxicity of 2-ME, may have significant implications for alternative treatment of advanced prostate cancer.
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PMID:2-methoxyestradiol blocks cell-cycle progression at G(2)/M phase and inhibits growth of human prostate cancer cells. 1147 20

Mammalian cells respond to DNA insults by activating cell-cycle checkpoints. This may result in a temporary cell growth arrest which allows DNA repair before proliferation or induces apoptosis. p53 is one of the main contributors in regulating these activities. To get a better insight on the molecular mechanism underlying these activities we studied the role of p53 in apoptosis and neurogenesis of brain cells from adult p53(+/+) or p53(-/-) mice exposed to gamma-irradiation. Apoptosis and neurogenesis were assessed up to 14 days following the injury. Five-ten hours following gamma-irradiation, cells with TUNEL positive nuclei were identified within the subgranular zone of dentate gyrus (DG) of both p53(+/+) and p53(-/-) mice. At the same time-points, pyknotic and shrinking nuclei were visualized by Hoechst 33258 staining. Furthermore, gamma-irradiation increased the number of proliferating cell nuclear antigen (PCNA) positive cells with a peak at 5-10 h in both animal groups. PCNA immunoreactivity was detected in cells exhibiting condensed nuclei as visualized by Hoechst 33258 staining. Neurogenesis, assessed by mitotic marker p34(cdc2) immunoreactivity, showed a biphasic response to gamma-irradiation both in p53(+/+) and p53(-/-) mice which was characterized by an early inhibition and a delayed stimulation. In p53(-/-) mice, the time required by DG granule cells to recover from the lesion and to stimulate proliferation was significantly shortened in comparison with wild-type mice thus resulting in an accelerated neurogenesis. Our data indicate that following gamma-radiation p53 plays a role in regulating cell-cycle progression rate but it is dispensable for promoting apoptosis of DG granule cells.
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PMID:p53 is dispensable for apoptosis but controls neurogenesis of mouse dentate gyrus cells following gamma-irradiation. 1153 41


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