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)

By crossing TG.AC v-Ha-ras and K6/ODC transgenic mice, we found previously that an activated ras and follicular ornithine decarboxylase (ODC) overexpression cooperate to generate spontaneous tumors in the skin. Cellular proliferation was dramatically increased in the K6/ODC transgenic skin, as evidenced by elevated proliferating cell nuclear antigen and Ki67 expression compared with nontransgenic littermates. Keratinocytes isolated from transgenic skin also displayed increased clonal growth. Paradoxically, expression of the growth inhibition-associated proteins p53, p21Waf1, p27Klp1, and Bax was increased with ODC overexpression in the skin. ODC overexpression did not affect cyclin D/cyclin-dependent kinase 4 (Cdk4)-dependent phosphorylation of retinoblastoma protein but stimulated cyclin E/Cdk2 and cyclin A/Cdk2-associated kinase activity, with minimal effect on the levels of these proteins. Thus, ODC/polyamine-induced activation of cyclin E/Cdk2 and cyclin A/Cdk2-associated kinase activity may cooperate with the ras induction of cyclin D/Cdk4/6-associated retinoblastoma protein phosphorylation to not only stimulate proliferation but ultimately contribute to tumor development.
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PMID:Effect of elevated levels of ornithine decarboxylase on cell cycle progression in skin. 1059 50

The cdk2 gene has been identified as a human cdc2/CDC28-related gene that encodes a protein kinase essential for the G1/S transition in mammalian cells, but not for the G2/M transition, which requires Cdk1, another p34cdc2/CDC28 homolog. Novel potential functions of Cdk2 have been uncovered by using two potent and specific inhibitors of its kinase activity, roscovitine and olomoucine, on human wt p53-expresser untransformed and tumor-derived cells. At concentrations equal or superior to respectively 30- and 20-fold their in vitro IC50 values for cyclin B/Cdk1, cyclin A/Cdk2 and cyclin E/Cdk2, the Cdk inhibitors precipitately induce a dramatic nuclear accumulation of wt p53 and a delocalization of nucleolin from the nucleolus in all interphase cells, whatever their cell cycle status, acting in this way like the DNA-damaging drug, mitomycin C (7 microg/ml). These early events are soon followed by a nucleolar fragmentation in both normal and tumor cells in the presence of the Cdk inhibitors but not in the presence of the DNA-damaging drug. Yet, treatment with either type of compounds eventually triggers rapidly the death of the tumor cells and, much more slowly, that of the normal cells. The Cdk inhibitors, however, stimulate cell death from any stage of the cell cycle, whereas the DNA-damaging drug kills more efficaciously S phase cells. These observations provide a hint that the Cdk2 kinase might be involved in controlling the nuclear levels of the tumor suppressor wt p53 protein and in maintaining the nucleolar integrity and function, linking in this way the cell division cycle machinery to survival functions and overall cell metabolism via the control of nucleocytoplasmic transport and of ribosome production.
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PMID:Potent inhibitors of cyclin-dependent kinase 2 induce nuclear accumulation of wild-type p53 and nucleolar fragmentation in human untransformed and tumor-derived cells. 1060

The CSF-1 receptor (CSF-1R) is expressed in >50% of human breast cancers. To investigate the consequence of CSF-1R expression, hormone-dependent human breast cancer cell lines, MCF-7 and T-47D, were transfected with CSF-1R. Unexpectedly, CSF-1 substantially inhibited estradiol (E2) and insulin-dependent proliferation of MCF-7 transfectants (MCF-7fms) and prevented cyclin E/cdk2 and cyclin A/cdk2 activation, consistent with a G1 arrest. In contrast, CSF-1 increased DNA synthesis in T-47D transfectants (T-47Dfms) alone and with E2 or insulin. In response to CSF-1, there was a marked and sustained upregulation of the cyclin-dependent kinase inhibitor, p21Waf1/Cip1, in MCF-7fms but not T-47Dfms. CSF-1 also markedly upregulated cyclin D1 in MCF-7fms. The coordinate increase in cyclin D1 and p21 had the effect of decreasing the specific but not absolute activity of cyclin D1/cdk4. p53 was not involved since CSF-1 induction of p21 was unaffected by dominant-negative p53 expression. ERK activation by CSF-1 was robust and sustained in MCF-7fms and to a much lesser extent in T-47Dfms. Using pharmacological and transient transfection approaches, we showed that ERK activation was necessary and sufficient for p21 induction in MCF-7fms. Moreover, activated MEK inhibited E2-stimulated cdk2 activity. Our findings indicate that the consequence of CSF-1R-mediated signals in human breast cancer cells is dependent on the genetic background of the particular tumor.
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PMID:CSF-1 activates MAPK-dependent and p53-independent pathways to induce growth arrest of hormone-dependent human breast cancer cells. 1060 7

We have previously demonstrated that hepatocyte proliferation induced by the mitogen 1,4-bis[2-(3,5-dichloropyridyloxy)] benzene (TCPOBOP) is independent of changes in cytokines, immediate early genes, and transcription factors that are considered to be necessary for regeneration of the liver after partial hepatectomy (PH) or necrosis. To further investigate the differences between mitogen-induced mouse hepatocyte proliferation and liver regeneration after PH, we have measured the expression of cyclin D1, cyclin D3, cyclin E, and cyclin A and of the cyclin-dependent kinases CDK2, CDK4, and CDK6. The involvement of the cyclin-dependent kinase inhibitors p21 and p27 and of the oncosuppressor gene p53 was also examined at different times after stimulation of hepatocyte proliferation. Results showed that a single administration of TCPOBOP caused a very rapid increase in the levels of cyclin D1, a G1 protein, when compared with two thirds PH (8 hours versus 30 hours). The early increase in cyclin D1 protein levels was associated with a faster onset of increased expression of S-phase-associated cyclin A (24 hours versus 36 hours with PH mice). Accordingly, measurement of bromodeoxyuridine (BrdU) incorporation revealed that, although approximately 8% of hepatocytes were BrdU-positive as early as 24 hours after TCPOBOP, no significant changes in BrdU incorporation were observed at the same time point after two thirds PH. The expression of other proteins involved in cell cycle control, such as cyclin-dependent kinases (CDK4, CDK2, CDK6), was also analyzed. Results showed that expression of CDK2 was induced much more rapidly in TCPOBOP-treated mice (2 hours) than in mice subjected to PH (36 hours). A different pattern of expression in the two models of hepatocyte proliferation, although less dramatic, was also observed for CDK4 and CDK6. Expression of the CDK inhibitors p21 and p27 and the oncosuppressor gene p53 variably increased after two thirds PH, whereas basically no change in protein levels was found in TCPOBOP-treated mice. The results demonstrate that profound differences in many cell cycle-regulatory proteins exist between direct hyperplasia and compensatory regeneration. Cyclin D1 induction is one of the earlier events in hepatocyte proliferation induced by the primary mitogen TCPOBOP and suggests that a direct effect of the mitogen on this cyclin may be responsible for the rapid onset of DNA synthesis observed in TCPOBOP-induced hyperplasia.
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PMID:Early increase in cyclin-D1 expression and accelerated entry of mouse hepatocytes into S phase after administration of the mitogen 1, 4-Bis[2-(3,5-Dichloropyridyloxy)] benzene. 1062 57

The intracellular metabolism of many carcinogenic polycyclic aryl hydrocarbons (PAHs, typified by the ubiquitous pollutant benzo[a]pyrene or B[a]P) generates electrophilic products that react covalently with genomic DNA. Cells that acquire PAH-induced DNA damage undergo growth arrest in a p53-independent manner (Vaziri, C., and Faller, D. V. (1997) J. Biol. Chem. 272, 2762-2769). In this report we have investigated the molecular basis of PAH-induced cell cycle arrest. Mitogenic signaling events involving cyclins D and E, Rb phosphorylation, and transcriptional activation of E2F-responsive genes (including cyclin E and cyclin A) were unaffected in cells containing PAH-damaged DNA. However, PAH-induced growth arrest was associated with post-transcriptional decreases in cyclin A expression. Mitogen-induced expression of cyclin B, an event that is temporally distal to cyclin A expression, was also inhibited in PAH-treated cells. The PAH-induced cell cycle block was transient, and arrested cells resumed DNA synthesis after a prolonged ( approximately 20 h) delay. Resumption of DNA synthesis in PAH-treated cells occurred concomitant with elevated expression of cyclins A and B. PAH-induced cell cycle arrest was overcome by ectopically expressed cyclin A (encoded by a recombinant adenovirus in transiently infected cells). Overall, our results suggest the existence of a DNA damage checkpoint pathway that arrests cell cycle progression via post-transcriptional control of cyclin A expression.
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PMID:A novel DNA damage checkpoint involving post-transcriptional regulation of cyclin A expression. 1063 67

The p53-inducible gene PC3 (TIS21, BTG2) is endowed with antiproliferative activity. Here we report that expression of PC3 in cycling cells induced accumulation of hypophosphorylated, growth-inhibitory forms of pRb and led to G(1) arrest. This latter was not observed in cells with genetic disruption of the Rb gene, indicating that the PC3-mediated G(1) arrest was Rb dependent. Furthermore, (i) the arrest of G(1)-S transition exerted by PC3 was completely rescued by coexpression of cyclin D1 but not by that of cyclin A or E; (ii) expression of PC3 caused a significant down-regulation of cyclin D1 protein levels, also in Rb-defective cells, accompanied by inhibition of CDK4 activity in vivo; and (iii) the removal from the PC3 molecule of residues 50 to 68, a conserved domain of the PC3/BTG/Tob gene family, which we term GR, led to a loss of the inhibition of proliferation as well as of the down-regulation of cyclin D1 levels. These data point to cyclin D1 down-regulation as the main factor responsible for the growth inhibition by PC3. Such an effect was associated with a decrease of cyclin D1 transcript and of cyclin D1 promoter activity, whereas no effect of PC3 was observed on cyclin D1 protein stability. Taken together, these findings indicate that PC3 impairs G(1)-S transition by inhibiting pRb function in consequence of a reduction of cyclin D1 levels and that PC3 acts, either directly or indirectly, as a transcriptional regulator of cyclin D1.
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PMID:Arrest of G(1)-S progression by the p53-inducible gene PC3 is Rb dependent and relies on the inhibition of cyclin D1 transcription. 1066 55

The fate of a neuron in the developing brain to multiply, differentiate, or die in an apoptotic manner depends on the expression of genes that are involved in regulating the cell cycle. Recent studies determined the involvement of several genes, including cyclin A and B2, in dopamine-induced apoptosis in cultured chick sympathetic neurons. Another gene that plays a role in apoptosis and differentiation of neurons, oligodendrocytes and PC12 cells is p53. It is also known that DNA damage increases p53 levels, triggering repair or apoptosis in response to moderate or severe damage, respectively. NMB cells express active and inducible forms of p53, thus being particularly suitable to analyze the role of this gene in dopamine-induced apoptosis and differentiation. The main observation of this work is that low concentrations of dopamine induce differentiation while high concentrations induce apoptosis, and that concentrations of dopamine that induce apoptosis increased p53 levels. There peak increase in p53 was within 3-6 h, before cell death. Thus, treatment with a high dopamine concentration may result in oxidation products and/or free radicals that heavily damage DNA, thus increasing p53 levels and initiating a cascade of events leading to apoptosis. Lower concentrations of dopamine apparently have a milder damaging effect on the DNA and induce growth arrest and differentiation. In various systems Bcl-2 inhibits cell death, being apoptotic or necrotic. Bcl-2, and other members of the family, such as Bax, are located downstream to p53 in the apoptotic pathway, and they contain negative or positive p53 response elements. Bcl-2 also protects cells by acting as antioxidant. Neuronal differentiation may be accompanied with an increase in Bcl-2, though it was suggested that the role of Bcl-2 in differentiation is less critical than in apoptosis. Herein, Bcl-2 was found to inhibit dopamine neurotoxicity. Whether the expression of Bcl-2 is regulated by different dopamine concentrations, or by dibutyryl-cAMP and DMSO, remains to be determined.
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PMID:Bcl-2 and p53: role in dopamine-induced apoptosis and differentiation. 1067 70

Entry into mitosis is controlled by the cyclin-dependent kinase CDK1 and can be delayed in response to DNA damage. In some systems, such G(2)/M arrest has been shown to reflect the stabilization of inhibitory phosphorylation sites on CDK1. In human cells, full G(2) arrest appears to involve additional mechanisms. We describe here the prolonged (>6 day) downregulation of CDK1 protein and mRNA levels following DNA damage in human cells. This silencing of gene expression is observed in primary human fibroblasts and in two cell lines with functional p53 but not in HeLa cells, where p53 is inactive. Silencing is accompanied by the accumulation of cells in G(2), when CDK1 expression is normally maximal. The response is impaired by mutations in cis-acting elements (CDE and CHR) in the CDK1 promoter, indicating that silencing occurs at the transcriptional level. These elements have previously been implicated in the repression of transcription during G(1) that is normally lifted as cells progress into S and G(2). Interestingly, we find that other genes, including those for CDC25C, cyclin A2, cyclin B1, CENP-A, and topoisomerase IIalpha, that are normally expressed preferentially in G(2) and whose promoter regions include putative CDE and CHR elements are also downregulated in response to DNA damage. These data, together with those of other groups, support the existence of a p53-dependent, DNA damage-activated pathway leading to CHR- and CDE-mediated transcriptional repression of various G(2)-specific genes. This pathway may be required for sustained periods of G(2) arrest following DNA damage.
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PMID:Repression of CDK1 and other genes with CDE and CHR promoter elements during DNA damage-induced G(2)/M arrest in human cells. 1071 60

Little is known about cell-cycle checkpoint activation by oxidative stress in mammalian cells. The effects of hyperoxia on cell-cycle progression were investigated in asynchronous human T47D-H3 cells, which contain mutated p53 and fail to arrest at G1/S in response to DNA damage. Hyperoxic exposure (95% O(2), 40-64 h) induced an S-phase arrest associated with acute inhibition of Cdk2 activity and DNA synthesis. In contrast, exit from G2/M was not inhibited in these cells. After 40 h of hyperoxia, these effects were partially reversible during recovery under normoxic conditions. The inhibition of Cdk2 activity was not due to degradation of Cdk2, cyclin E or A, nor impairment of Cdk2 complex formation with cyclin A or E and p21(Cip1). The loss of Cdk2 activity occurred in the absence of induction and recruitment of cdk inhibitor p21(Cip1) or p27(Kip1) in cyclin A/Cdk2 or cyclin E/Cdk2 complexes. In contrast, Cdk2 inhibition was associated with increased Cdk2-Tyr15 phosphorylation, increased E2F-1 recruitment, and decreased PCNA contents in Cdk2 complexes. The latter results indicate a p21(Cip1)/p27(Kip1)-independent mechanism of S-phase checkpoint activation in the hyperoxic T47D cell model investigated.
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PMID:Hyperoxia induces S-phase cell-cycle arrest and p21(Cip1/Waf1)-independent Cdk2 inhibition in human carcinoma T47D-H3 cells. 1077 7

In a previous work we have reported evidences on the mitogenic activity of urokinase-type and tissue-type plasminogen activator (u-PA, t-PA) on serum-deprived human dermal fibroblasts. In this work we have studied the transcription-dependent changes of some cell-cycle related genes associated with the biological activity of PAs, as well as the possible involvement of protein tyr kinases (PTK) and/or protein kinase C (PKC) in the mitogenic signal transduction. The data obtained demonstrate that the growth factor activity of PAs is associated with: - a rapid transient activation of early response genes, c-fos, c-jun and c-myc; - the subsequent coordinated down-regulation of p53 and p21CIP1; - the constant expression of the MEK1 mRNA in every phase of the cell cycle. Quiescent (G0) cells did not express c-fos, c-jun, c-myc and cyclin A, but upon stimulation with mitogens (fetal calf serum (FCS), u-PA, t-PA) the cyclin A mRNA expression was observed in concomitance with the activation of DNA synthesis. Therefore u-PA, t-PA and FCS similarly modulate the expression of c-fos, c-jun, c-myc, p53, p21CIP1 and cyclin A with only slight differences likely related to the time required for activation of DNA synthesis. The PAs mitogenic stimulation of serum-starved cells was associated with the internalization of their molecules, as revealed by immunostaining. The biological activity of u-PA, t-PA, as well as that of limiting concentration of FCS (1%), was mediated by PTK and PKC. Conversely, PTK, but not PKC, was involved in the activation of the proliferative response of basic fibroblast growth factor in the same experimental conditions. In conclusion, u-PA and t-PA can utilize two different pathways, one depending on PTK and the other on PKC in a way similar to the mitogenic activity induced by low concentration of FCS (1%).
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PMID:Gene response of human skin fibroblasts to urokinase- and tissue-type plasminogen activators. 1080 Oct 75


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