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)

Ceramide acts as a mediator of programmed cell death in various cell types, but its molecular mechanisms linked to the cell cycle are poorly understood. In this study, we investigated the expression of the p21 gene and its relationship to apoptosis induced by ceramide. In SK-HEP-1 cells, the addition of C6-ceramide resulted in a dose- and time-dependent growth suppression and DNA fragmentation characteristics of apoptosis. p21 protein was induced during that process, while the protein level of p53, known as a transcriptional activator of p21, was not elevated under the same condition. This apoptotic cell death with p21 induction was also observed in the Hep 3B cells lacking functional p53 after exposure to C6-ceramide. These findings suggest that ceramide-induced apoptosis is associated with the upregulation of p21 mRNA and protein in a p53-independent pathway.
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PMID:Induction of p21 during ceramide-mediated apoptosis in human hepatocarcinoma cells. 971 64

Topotecan is a novel topoisomerase I inhibitor that may have a role in the adjuvant chemotherapy of several solid tumors, including malignant glioma. Here, we have characterized the time- and concentration-dependent toxicity of topotecan in four human malignant glioma cell lines, LN-18, LN-229, LN-308 and T98G. High micromolar concentrations of topotecan, which are unlikely to be achieved in plasma in human patients in vivo, were cytotoxic within 48 hr, induced DNA fragmentation, did not induce major cell cycle changes, failed to consistently alter BCL-2 or BAX protein levels but inhibited RNA synthesis and induced cleavable DNA/topoisomerase I complex formation. Prolonged exposure for 72 hr to high nanomolar to low micromolar concentrations of topotecan augmented p21 protein levels and induced G2/M arrest but failed to consistently alter BCL-2 and BAX protein levels, did not induce significant DNA/topoisomerase I complex formation and did not inhibit RNA synthesis. Neither short-term nor long-term topotecan toxicity was blocked by ectopic expression of bcl-2 or wild-type p53. Transfer of a mutant p53 gene enhanced topotecan sensitivity in wild-type p53 LN-229 but not mutant p53 LN-18 cells. CD95 ligand (CD95L)-induced apoptosis was synergistically enhanced by short-term/high concentration but not long-term/low concentration exposure to topotecan, suggesting that topotecan sensitizes human malignant glioma cells to CD95L-induced apoptosis via inhibition of RNA synthesis. These data suggest that topotecan needs to be administered in high concentrations, such as an intratumoral polymer, to limit glioma cell growth in synergy with CD95L in vivo.
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PMID:Potentiation of CD95L-induced apoptosis of human malignant glioma cells by topotecan involves inhibition of RNA synthesis but not changes in CD95 or CD95L protein expression. 973

We previously reported that deferoxamine, an iron chelating agent, induced p53 and cell accumulation in the G1 phase of ML-1 cells in the same way as the DNA damaging agent, etoposide. Etoposide treatment increased expression of the p21 gene, a cyclin kinase inhibitor, at both the mRNA and protein levels. However, deferoxamine treatment only increased the p21 mRNA level without the appearance of a detectable protein product. A substrate for cyclin kinase, pRB, was unphosphorylated by etoposide treatment, but remained unaffected by deferoxamine, indicating that p21 was functional after etoposide, but not after deferoxamine treatment. Therefore, in the present study, we investigated the involvement of the ubiquitin proteasome pathway in post-transcriptional regulation of p21. By the addition of lactacystin, a proteasome inhibitor, to deferoxamine treatment, the level of unubiquitinated p21 protein product was similar to that induced by etoposide treatment, and the ubiquitinated p21 bands became apparent. After etoposide treatment, the level of ubiquitinated p21 was diminished and a high level of unubiquitinated p21 expression was observed. We concluded that (1) efficient expression of p21 protein requires inhibition of the ubiquitin-proteasome pathway, and (2) DNA damage inhibits the ubiquitination of p21.
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PMID:DNA damage induces p21 protein expression by inhibiting ubiquitination in ML-1 cells. 973 69

The 'high risk' human papillomaviruses are associated with the development of anogenital carcinomas and their E6 and E7 genes possess immortalizing and transforming functions in several in vitro culture systems. Recently the E6 gene has also been shown to enhance the apoptosis of human mammary epithelial cells. To determine the apoptotic activity of these oncogenes in the natural host cell, we infected genital keratinocytes with retroviruses expressing either HPV-16 E6, E7, or both the E6 and E7 (E6/7) genes. Apoptosis was quantitated under normal growth conditions or when induced by tumor necrosis factor alpha/cycloheximide or sulfur mustard. In contrast to previous findings with mammary epithelial cells, the E6 gene did not significantly augment either spontaneous or induced apoptosis. E6 also did not suppress apoptosis in normal keratinocytes (despite dramatically reducing their p53 levels), suggesting that p53-independent events mediated this effect. In contrast, E7 increased both spontaneous and induced apoptosis as well as the cellular levels of p53 and p21 protein. Interestingly, co-expression of E6 abrogated E7-facilitated apoptosis by tumor necrosis factor alpha nearly completely, but had only a minor protective effect on sulfur mustard induced apoptosis in these cells, demonstrating at least in part the p53-dependence and -independence of these two apoptotic pathways. Finally, our results indicate that the apoptosis of normal and E7-expressing keratinocytes is differentially affected by E6 expression and that E7, when unaccompanied by E6, sensitizes keratinocytes to apoptosis.
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PMID:The E7 protein of human papillomavirus type 16 sensitizes primary human keratinocytes to apoptosis. 977 63

p21 protein has been reported to be a critical downstream effector of p53 and a potent inhibitor of cyclin-dependent kinases. Thus, the p21 gene is thought to play a central role in tumor suppression. In this study we investigated p21 protein expression and mutation in gastric adenocarcinoma. A total of 76 primary gastric carcinoma specimens were immunohistochemically stained for p21 protein expression and evaluated the correlations between p21 expression and clinicopathologic features. In a proportion of them (20 cases), we also analyzed the possible presence of p21 gene mutations using PCR-SSCP method. Fourty seven out of 76 cases (61.8%) were p21-negative, and the remaining twenty nine cases (38.2%) were p21 -positive on immunostains. There was a correlation between the expression of p21, and the depth of tumor invasion and lymph node metastasis (p<0.05). No mutation of the p21 gene was detected in all of 20 tumor tissues. These results suggest that the status of p21 expression may have prognostic value in gastric adenocarcinoma.
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PMID:p21 expression and mutation in gastric carcinoma: analysis by immunohistochemistry and PCR-SSCP. 981 Nov 80

Suramin is an antineoplastic agent which has a cytostatic effect on both normal and tumor-derived cells. We have investigated whether the induction of growth arrest by suramin requires the p53 protein, a tumor suppressor gene product involved in the initiation of growth arrest following DNA damage. Activation of the p53 protein by genotoxic agents causes increased p53 protein levels and p53-dependent transcription of the p21 gene. The p21 protein then inhibits cyclin-dependent kinases, initiating G1 arrest. Exposure of NIH-3T3 cells to suramin caused a rapid (1-2 h) increase in the level of p53-DNA-binding activity. Flow cytometric analysis indicated that suramin arrested NIH-3T3 cells in G0-G1. However, suramin did not increase the p53-dependent transcription of the p21 gene or inhibit cyclin-dependent kinase 2 kinase activity. If NIH-3T3 cells were exposed to radiation or suramin plus radiation, p21 mRNA levels were increased and cyclin-dependent kinase 2 kinase activity was inhibited, indicating that suramin does not block the cells' ability to increase p21 levels. To determine whether the G0-G1 arrest induced by suramin required p53, NIH-3T3 cells transfected with a dominant negative mutant p53 gene to eliminate wild-type p53 function (NMP cells) were exposed to suramin. NMP cells still exhibited G0-G1 arrest after suramin treatment. Suramin increases p53 protein levels, but fails to increase p21 mRNA levels or to activate the G1 checkpoint. These data suggest that suramin induces growth arrest in NIH-3T3 cells by a mechanism that is independent of cellular p53 status.
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PMID:Suramin increases p53 protein levels but does not activate the p53-dependent G1 checkpoint. 981 69

p21 protein (p21) inhibitor of cyclin-dependent kinases is a critical downstream effector in the p53-specific pathway of growth control and can also be induced by p53-independent pathways in relation to terminal differentiation. We investigated p21 immunoreactivity in 261 breast carcinomas (141 node negative and 120 node positive) with long-term follow-up (median, 73 months; range, 37-119). p21 was seen in 214 (82%) infiltrating tumors, staining was nuclear and heterogeneous, and the p21 labeling index ranged from 0 to 90%. Sixty-eight (32%) patients showed p21 overexpression (>10% of reactive tumor cells). p21 overexpression was associated with large tumor size, positive nodal status, high histological grade, and high mitotic count and was related to short disease-free survival (DFS) in the whole series of patients (P = 0.04), in the node-negative subgroup (P = 0.004), and in the group of patients who did not undergo systemic adjuvant therapy (P = 0.003). In patients treated with systemic adjuvant therapy, bivariate analysis of the combined p21 and p53 phenotypes showed that p21+/p53+ tumors were associated with long DFS and overall survival (OS), whereas p21-/p53+ tumors had the worst prognosis. In treated patients, multivariate analysis showed that the p21-/53+ phenotype was independently associated with short DFS and OS. Our present data support the hypothesis that p21/p53 heterogeneous expression may be of clinical relevance for the therapeutic response to chemotherapy/hormonotherapy. The p21-/p53+ phenotype could correspond to a situation where p53 overexpression really reflects complete abrogation of p53 function. These cases with disrupted p53 function should have impaired the G1 checkpoint and may not be able to activate the apoptotic cascade in response to DNA-damaging drugs.
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PMID:Prognostic value of p21(WAF1) and p53 expression in breast carcinoma: an immunohistochemical study in 261 patients with long-term follow-up. 981 38

The cyclin-dependent kinase (CDK) inhibitor p21(Cip1/Waf1) plays an essential role in the control of cell proliferation by modulating the activity of cyclin/CDK complexes in response to various intracellular or extracellular signals. Small variations in p21 expression levels may determine whether it acts as an inhibitor or an assembly factor for cyclin/CDK complexes. It is therefore critical to better characterize the mechanisms regulating p21 abundance. Here, we show, using a tetracycline-regulated system in p53-deficient DLD-1 human colon cancer cells, that p21 protein levels and stability are regulated by the proteasome-dependent degradation pathway and by association with its partners, CDKs and PCNA. A p21 mutant deficient for interaction with CDKs, p21CDK-, displayed an enhanced stability and greatly reduced sensitivity to proteasome-mediated proteolysis, indicating that association with cyclin/CDK complexes may trigger p21 degradation. In contrast, a p21 mutant impaired in the interaction with PCNA, p21PCNA-, exhibited a decreased stability, suggesting that association with PCNA protects p21 from proteasome-dependent degradation. Furthermore, the abundance of p21 itself, in addition to protein-protein interactions, may also modulate p21 stability since we found that high levels of p21 expression overcome proteasome-dependent regulation of p21 accumulation.
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PMID:Interaction with cyclin-dependent kinases and PCNA modulates proteasome-dependent degradation of p21. 982 54

The authors examined the growth response of cardinal ligamental fibroblasts derived from patients with prolapsus uteri (HPLiF) and compared it with the response of those from control subjects (HCLiF). The growth rate during the logarithmic growth phase was not different between HPLiF and HCLiF, while the cell density at confluence (saturation density) was significantly higher in HPLiF than in HCLiF. When added alone, platelet-derived growth factor (PDGF), insulin-like growth factor-I (IGF-I), and epidermal growth factor (EGF) produced minimal effects on DNA synthesis in HCLiF. The simultaneous addition of PDGF, IGF-I and EGF synergistically stimulated the DNA synthesis. In contrast, PDGF alone was able to initiate DNA synthesis in HPLiF. The combination of PDGF, IGF-I, and EGF significantly stimulated the DNA synthesis of HPLiF compared with HCLiF. p53 protein and p53 gene transcripts decreased by 50% in HPLiF. The anti-WAF1 antibody reacted intensely with a 21-kDa protein in the homogenates of control fibroblasts, while the immunoreactive band in prolapsus fibroblasts was clearly reduced. These results indicate that the higher proliferative activity at near confluency in prolapsus fibroblasts may result from the decreased expression of p53 protein and p53 mRNA followed by the decrease in p21 protein. Furthermore, the failure of cells to enter quiescence may lead to a decrease in the synthesis and deposition of elastin and thus may contribute to the loss of supportive function in uterine connective tissues.
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PMID:Decrease in p53 protein in cultured cardinal ligament fibroblasts from patients with prolapsus uteri. 982 80

During a normal cell cycle, entry into S phase is dependent on completion of mitosis and subsequent activation of cyclin-dependent kinases (Cdks) in G1. These events are monitored by checkpoint pathways. Recent studies and data presented herein show that after treatment with microtubule inhibitors (MTIs), cells deficient in the Cdk inhibitor p21(Waf1/Cip1) enter S phase with a >/=4N DNA content, a process known as endoreduplication, which results in polyploidy. To determine how p21 prevents MTI-induced endoreduplication, the G1/S and G2/M checkpoint pathways were examined in two isogenic cell systems: HCT116 p21(+/+) and p21(-/-) cells and H1299 cells containing an inducible p21 expression vector (HIp21). Both HCT116 p21(-/-) cells and noninduced HIp21 cells endoreduplicated after MTI treatment. Analysis of G1-phase Cdk activities demonstrated that the induction of p21 inhibited endoreduplication through direct cyclin E/Cdk2 regulation. The kinetics of p21 inhibition of cyclin E/Cdk2 activity and binding to proliferating-cell nuclear antigen in HCT116 p21(+/+) cells paralleled the onset of endoreduplication in HCT116 p21(-/-) cells. In contrast, loss of p21 did not lead to deregulated cyclin D1-dependent kinase activities, nor did p21 directly regulate cyclin B1/Cdc2 activity. Furthermore, we show that MTI-induced endoreduplication in p53-deficient HIp21 cells was due to levels of p21 protein below a threshold required for negative regulation of cyclin E/Cdk2, since ectopic expression of p21 restored cyclin E/Cdk2 regulation and prevented endoreduplication. Based on these findings, we propose that p21 plays an integral role in the checkpoint pathways that restrain normal cells from entering S phase after aberrant mitotic exit due to defects in microtubule dynamics.
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PMID:p21(Waf1/Cip1) inhibition of cyclin E/Cdk2 activity prevents endoreduplication after mitotic spindle disruption. 985 45


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