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)

Current therapy for advanced prostate cancer is largely based on androgen deprivation and is mostly palliative because all patients eventually relapse with androgen-independent disease. Doxorubicin (Dx), an anthracycline used commonly as a chemotherapeutic agent in relapsed prostate cancer, is a strong inducer of p53 expression and p21(CIP1/WAF1) (p21) transactivation. Previous reports suggest that p21 may have a role in the modulation to chemotherapy-induced apoptosis, prostate cancer progression and androgen regulation. In order to investigate if p21 has a pro-survival role in the response of prostate cancer cells to cellular stress, we exposed two androgen-regulated human prostate cancer cell lines (MDA PCa 2b and LNCaP) to Dx and growth factor withdrawal. We then studied expression of p53 and p21, cell-cycle kinetics and apoptosis. We have found that p53 protein accumulated in a dose- and time-dependent manner after Dx treatment, while p21 expression increased over time with low but decreased with high Dx doses. Apoptosis occurred in parallel with p21 down-modulation. Dx treatment of p53 knockout cells demonstrated that p21 induction was strictly p53 dependent. Reduction of p21 levels in prostate cancer cells with an antisense p21 adenovirus resulted in sensitization to Dx and accelerated onset of apoptosis in response to growth factor withdrawal. The evidence presented here also suggests that caspase activation mediates the apoptosis in this system and supports that p21 may modulate the threshold of apoptosis in prostate cancer. These observations may thus provide implications onto the integration of chemotherapy and androgen ablation.
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PMID:p21 modulates threshold of apoptosis induced by DNA-damage and growth factor withdrawal in prostate cancer cells. 1215 46

Foxk1 is a forkhead/winged helix transcription factor that is restricted to myogenic progenitor cells in adult skeletal muscle. Mice lacking Foxk1 (Foxk1-/-) display growth retardation and a severe impairment in skeletal muscle regeneration following injury. Here we show that myogenic progenitor cells from Foxk1-/- mice are reduced in number and have perturbed cell cycle progression (G(0)/G(1) arrest). Molecular analysis of Foxk1-/- myogenic progenitor cells revealed increased expression of the cyclin-dependent kinase inhibitor, p21(CIP), independent of changes in other cell cycle inhibitors, including p53. Combinatorial mating of Foxk1-/- mice with p21(CIP)-/- mice, to generate double mutant progeny, resulted in a complete restoration of the growth deficit, skeletal muscle regeneration, myogenic progenitor cell number, and cell cycle progression that characterized the Foxk1-/- mice. We conclude that Foxk1 is essential for regulating cell cycle progression in the myogenic progenitor cell and that the cyclin-dependent kinase inhibitor, p21(CIP), may be a downstream target of Foxk1.
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PMID:Absence of p21CIP rescues myogenic progenitor cell proliferative and regenerative capacity in Foxk1 null mice. 1244 8

Members of the cadherin family have been implicated as growth regulators in multiple tumor types. Based on recent studies from our laboratory implicating T-cadherin expression in mouse brain tumorigenesis, we examined the role of T-cadherin in astrocytoma growth regulation. In this report, we show that T-cadherin expression increased during primary astrocyte physiologic growth arrest in response to contact inhibition and serum starvation in vitro, suggesting a function for T-cadherin in astrocyte growth regulation. We further demonstrate that transient and stable reexpression of T-cadherin in deficient C6 glioma cell lines results in growth suppression. In addition, T-cadherin-expressing C6 cell lines demonstrated increased homophilic cell aggregation, increased cell attachment to fibronectin, and decreased cell motility. Cell cycle flow cytometry demonstrated that T-cadherin reexpression resulted in G2 phase arrest, which was confirmed by mitotic index analysis. This growth arrest was p53 independent, as T-cadherin could still mediate growth suppression in p53(-/-) mouse embryonic fibroblasts. T-cadherin-expressing C6 cell lines exhibited increased p21(CIP1/WAF1), but not p27(Kip1), expression. Lastly, T-cadherin-mediated growth arrest was dependent on p21(CIP1/WAF1) expression and was eliminated in p21(CIP1/WAF1)-deficient fibroblasts. Collectively, these observations suggest a novel mechanism of growth regulation for T-cadherin involving p21(CIP1/WAF1) expression and G2 arrest.
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PMID:T-cadherin-mediated cell growth regulation involves G2 phase arrest and requires p21(CIP1/WAF1) expression. 1250 55

Green tea polyphenols (GTPs), which possess antioxidant properties, have been shown to inhibit the development of atherosclerotic lesions. Epigallocatechin-3-gallate (EGCG), the most abundant GTP, displays antiproliferative effects in a variety of cell types. Here, we examined the effects of GTPs on aortic smooth muscle cell (SMC) proliferation. Treatment with a GTP mixture or EGCG at a dose of 40 to 50 microg/ml slowed SMC growth, while at a higher dose of 80 microg/ml EGCG also induced cell death as judged by TUNEL assay. Apoptosis was mainly observed in proliferating SMCs in subconfluent cultures; whereas at higher confluency, cell viability was largely unaffected. Treatment with 80 microg/ml EGCG induced the tumor suppressor p53, which was functional as judged by activation of the target cyclin-dependent kinase inhibitor p21CIP1. Inhibition of p53 activity with a dominant negative mutant reduced cell death. The increase in p53 protein was due to increased stability. EGCG also induced functional nuclear factor-kappaB (NF-kappaB) complexes, and inhibition of this activity reduced the extent of cell death. Thus, EGCG inhibits growth and induces death of SMCs in a p53- and NF-kappaB-dependent manner. These results provide evidence for a new molecular mechanism whereby green tea polyphenols inhibit SMC proliferation and function to prevent the development of atherosclerosis.
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PMID:Green tea polyphenol epigallocatechin-3 gallate induces apoptosis of proliferating vascular smooth muscle cells via activation of p53. 1258 42

Apart from their coordinated inactivation by DNA tumor viral oncoproteins, the pRB and p53 tumor suppressor pathways were not known to be connected ten years ago. Within the last decade, our appreciation of how these pathways are interconnected has grown substantially. The checks and balances that exist between pRB and p53 involve the regulation of the G1/S transition and its checkpoints, and much of this is under the control of the E2F transcription factor family. Following DNA damage, the p53-dependent induction of p21CIP1 regulates cyclin E/Cdk2 and cyclin A/Cdk2 complexes both of which phosphorylate pRB, leading to E2F-mediated activation. Similarly, E2F1-dependent induction of p19ARF antagonizes the ability of mdm2 to degrade p53, leading to p53 stabilization and potentially p53-mediated apoptosis or cell cycle arrest. From the existing mouse models discussed above, we also know that proliferation, cell death and differentiation of distinct tissues are also intimately linked through entrance and exit from the cell cycle, and thus through pRB and p53 pathways. Virtually all human tumors deregulate either the pRB or p53 pathway, and often times both pathways simultaneously, which is critical for crippling cellular defense against neoplasia. The next decade of cancer research will likely see these two tumor suppressor pathways only merge even more.
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PMID:Role of the RB tumor suppressor in cancer. 1261 99

Phenylacetate is a differentiation agent and has anticancer activity with relatively low toxicity. In the present study, we examined the anticancer effect of six synthetic phenylacetate derivatives in human lung cancer cells in our search for more effective phenylacetate analogous. Results showed that the antiproliferative effects of these synthetic compounds were stronger than those of phenylacetate, and that N-butyl-2-(2-fluorolphenyl)acetamide (SCK6) is the most potent compound. To address the mechanism of the antiproliferative effect of SCK6, cell cycle analysis was performed. Result showed that SCK6 (1 mM) induced G(1) arrest in CH27 cells. Western blot analysis of G(1) phase regulatory proteins demonstrated that the protein levels of cyclin-dependent kinase 2 (Cdk2), Cdk4, Cyclin E and Cyclin D3 were decreased after treatment with SCK6 but not those of Cdk6, Cyclin D1 and D2. In contrast, SCK6 increased the protein levels of p53 and p21(CIP1/WAF1). Data from in situ terminal transferase-mediated dUTP-fluorescensin nick end-labeling (TUNEL) assay and DNA fragmentation analysis demonstrated that SCK6 induced apoptotic cell death in CH27 cells. This SCK6-induced apoptosis was accompanied by a downregulation of Bcl-2 protein and activation of the caspase-9 cascade. Overexpression of Bcl-2 by adeno-Bcl-2 vector infection significantly inhibited SCK6-induced apoptosis. Moreover, treatment with caspase inhibitors also markedly reduced cell death induced by SCK6. Taken together, these results suggest that downregulation of G(1)-associated Cdks and cyclins and upregulation of p53 and p21(CIP1/WAF1) may contribute to SCK6-mediated G(1)-phase arrest. Furthermore, the decrease in Bcl-2 and the activation of caspase-9/caspase-3 may be the effector mechanism through which SCK6 induces apoptosis.
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PMID:A phenylacetate derivative, SCK6, inhibits cell proliferation via G1 cell cycle arrest and apoptosis. 1270 52

One of the most frequent malignancies in humans is lung adenocarcinoma.To develop novel diagnostic and therapeutic approaches for the management of this disease, animal models are required. We have used transgenic mice with lung-targeted expression of the CRaf kinase to evaluate genes altered frequently in human lung adenocarcinoma for their effect on tumor progression. Here we report that loss of p53 dramatically accelerates tumor development and induces a phenotypic switch in the target cell from cuboid to a nonciliated columnar morphology. Coexpression of lung epithelial cell markers surfactant protein C and Clara cell antigen suggests that tumor cell dedifferentiation could be involved in this process. The effect of p53 is specific, because loss of one of its target genes, p21(CIP1/WAF1), did not have this effect on cell phenotype although tumor latency was also reduced significantly. Neither loss of p53 nor p21 stimulated acquisition of the metastasis program beyond the stage of bronchiolar extension. This mouse model for pulmonary adenoma and adenocarcinoma should be very helpful for a better understanding of pathogenesis and treatment of this most deadly human cancer.
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PMID:Loss of p53 in craf-induced transgenic lung adenoma leads to tumor acceleration and phenotypic switch. 1272 49

Iron (Fe) chelators are potential antitumor agents. Cellular Fe depletion results in a G1/S arrest but the precise molecular mechanisms involved remain unclear. Recent studies have shown that this process is complex with multiple cell cycle molecules being involved. We previously showed that Fe chelators such as 2-hydroxy-1-naphthylaldehyde isonicotinoyl hydrazone (311) were far more potent antitumor agents than the clinically used ligand, desferrioxamine (DFO). To further characterize the effects of chelators on cell cycle arrest, we compared their activity with the DNA-damaging agents actinomycin D (Act D) and cisplatin (CP). These latter two compounds increase the expression of p53 and its target genes such as the universal cyclin-dependent kinase inhibitor, p21(CIP1/WAF1). Incubation of normal and neoplastic cells with all agents resulted in increased nuclear p53, the effect being pronounced for Act D and CP. As expected, both Act D and CP also markedly increased nuclear p21(CIP1/WAF1) protein levels, while DFO and 311 caused a significant (P<0.0004) decrease. This latter effect was surprising, as these chelators markedly increased mRNA levels of this molecule. Immunofluorescence studies showed that Act D and CP caused nuclear localization of p21(CIP1/WAF1). In contrast, the chelators prevented translation of p21(CIP1/WAF1). This did not appear to be due to a general effect of the chelators on preventing translation, as transferrin receptor 1 was markedly up-regulated 15- to 21-fold by DFO and 311. Combination of 311 with Act D or CP prevented translation of p21(CIP1/WAF1) and its nuclear localization observed with these DNA-damaging agents. Significantly, the effect of chelation on reducing nuclear p21(CIP1/WAF1) was reversed by the Fe donor ferric ammonium citrate, indicating that p21(CIP1/WAF1) translation was dependent on intracellular Fe levels. This study demonstrates that while Fe chelators markedly up-regulate the mRNA levels of p21(CIP1/WAF1) they paradoxically inhibit translation.
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PMID:Potent iron chelators increase the mRNA levels of the universal cyclin-dependent kinase inhibitor p21(CIP1/WAF1), but paradoxically inhibit its translation: a potential mechanism of cell cycle dysregulation. 1280 43

Mutations in the p53 and retinoblastoma (pRb) pathways associated with the use of tobacco and alcohol are common in squamous cell carcinoma (SCC) of the head and neck. Cell cycle proteins are also affected by human papillomavirus (HPV), which may also have an aetiological role in cancers at particular sites, most notably the tonsil. Attempts to identify prognostic molecular markers in head and neck cancers have met with conflicting results, but few studies have been undertaken with tumours of known HPV status at a single anatomic site. In our study 86 tonsil cancers were analysed for HPV status by sequence analysis of polymerase chain reaction products and for the expression of cell cycle proteins (p53, p21(CIP1/WAF1), pRb, p16(INK4A), cyclin D1 and p27(KIP1)) by immunohistochemistry. The HPV status could be established in 67 of the tumours. Thirty-one (46%) of these were HPV-positive, predominantly (28/31) for HPV16. Findings were related to tumour recurrence and patient survival. None of the cell cycle proteins independently predicted recurrence or survival. Patients with HPV-positive tumours, however, were significantly less likely (p < 0.05) to have recurrence or to die of disease than those with HPV-negative tumours, after adjusting for the effects of the cell cycle proteins, clinical stage, pathological node status, tumour grade, age, gender and treatment. These findings support the concept that HPV-positive tonsil cancers may be a distinct biological group with less aggressive characteristics. Screening of tonsil cancers for HPV DNA may help optimise treatment and provide more accurate prognostic information.
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PMID:Human papillomavirus positivity predicts favourable outcome for squamous carcinoma of the tonsil. 1284 51

Iron (Fe) chelators induce a G1/S arrest and several of these are undergoing clinical trials as anticancer agents. Despite this, little is known concerning the precise function of Fe in cell cycle progression and the role of p53 in this process. The aim of this study was to assess the effect of Fe chelators on p53 and the mechanism involved in the chelator-mediated increase in mRNA levels of the universal cyclin-dependent kinase inhibitor p21CIP1/WAF1. Cells were incubated with the potent Fe chelator 2-hydroxy-1-naphthylaldehyde isonicotinoyl hydrazone (311) and the results compared with those from cells treated with actinomycin D (Act D), which induces p53. Following incubation with 311, a 3- to 5-fold increase in nuclear p53 protein was observed in cells with wild-type p53. In addition, 311 increased p53 DNA-binding activity 2-fold, while Act D increased it 3- to 5-fold in cells with native p53. To determine the role of p53 in WAF1 transcription, a reporter construct was used consisting of a WAF1 promoter containing the p53-binding site. In cells with wild-type p53, chelators had no effect on luciferase activity, while the positive control, Act D, caused a significant increase. Hence, despite increased p53 protein expression and p53 DNA-binding activity following chelation, these latter results suggested it had no role in up-regulating WAF1 mRNA. Our experiments demonstrated: (i) that the elevated WAF1 mRNA expression after Fe chelation was due to increased transcription and also to a post-transcriptional mechanism that was sensitive to cycloheximide; and (ii) that Fe-chelation increased WAF1 expression through a p53-independent pathway.
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PMID:The effect of potent iron chelators on the regulation of p53: examination of the expression, localization and DNA-binding activity of p53 and the transactivation of WAF1. 1286 19


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