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

p21waf1/cip1 protein, an inhibitor of cyclin dependent kinases, is a critical downstream target in the p53-specific pathway of growth control, and can also be induced by p53 independent pathways in relation to terminal differentiation. p21waf1 is also a putative tumour suppressor. Hence, we sought to determine whether this protein is abnormally expressed during betel- and tobacco-related oral oncogenesis. The aim was to determine whether a correlation exists between the expression profile of p21 and clinicopathological parameters of the patients, as well as with their p53 status. Immunohistochemical analysis showed that the expression of p21 protein in premalignant lesions was consistently elevated in the superficial, differentiated cells of the epithelium, while overexpression of the p53 tumour suppressor gene was observed in the basal proliferating layers of the epithelium. Our study demonstrated that p21 overexpression is associated with differentiation in proliferating dysplasias and squamous cell carcinomas (SCCs). The expression of p21 and p53 proteins was observed in 11/25 premalignant lesions. In 7 of these 11 cases, a heterogenous pattern of expression of p21 and p53 was observed. Four of these 11 premalignant and 30/51 malignant lesions showed concordant expression of both p21 and p53 proteins. The discordant p21 +/p53- phenotype was observed in 4/25 premalignant lesions and 5/51 oral SCCs. The p21-/p53+ phenotype was observed in 5/25 premalignant lesions and 7/51 oral SCCs. These results suggest that induction of p21 occurs by both p53 dependent and independent mechanisms during oral tumorigenesis.
 ...
PMID:Expression of cyclin dependent kinase inhibitor p21waf1/cip1 in premalignant and malignant oral lesions: relationship with p53 status. 986 40

Current therapy for glioma is suboptimal. The transfer of apoptosis genes to tumors constitutes one of the most promising strategies for cancer gene therapy. We have previously shown that massive apoptosis occurs when wild-type p53 or E2F-1 expression is induced in glioma. However, the mechanism of action and the efficiency in inducing apoptosis of these two proteins are not similar. Adenovirus-mediated p53 gene transfer is ineffective in causing apoptosis in glioma cells that retain wild-type p53 genotype or overexpress the p21 protein. The p16/Rb/E2F pathway is the most frequent target of genetic alterations in gliomas, and therefore constitutes a suitable target for gene therapy strategies. However, the transfer of either the p16 or Rb gene to glioma cells results in cytostatic effect. The E2F-1 protein is able to induce generalized apoptosis in gliomas independently of the p53, p16 or Rb status. In addition, p21- or p16-mediated growth arrest did not protect glioma cells from E2F-1-mediated apoptosis. The apoptotic molecule bax is induced in p53-mediated apoptosis, but bax is not induced in E2F-1-mediated apoptosis in glioma cells. Careful selection of patients may be necessary before designing therapeutic strategies using either p53 or E2F-1 as a therapeutic tools for glioma patients.
 ...
PMID:Gene therapy for gliomas: p53 and E2F-1 proteins and the target of apoptosis. 986 90

p53 protein, a product of the p53 cancer suppressor gene, and p21 protein, a cyclin-dependent kinase inhibitor, were immunohistochemically investigated in 150 oral squamous cell carcinomas (SCCs) and the relationship between their expression and clinicopathological findings were evaluated. The positivity for p53 and p21 proteins was not correlated with the T-stage, mode of tumor cell invasion or tumor cell differentiation. However, the expression of p53 and p21 proteins was correlated with lymph node metastasis. Of 62 SCCs with regional lymph node metastasis, 45 SCCs (72.6%) were positive for p53 while 45 (52.9%) of 88 SCCs without metastasis expressed p53 protein (p < 0.02). In addition, p21 protein was observed in 25 (38.5%) and 18 (21.2%) SCCs with and without metastasis, respectively (p < 0.05). Furthermore, p53 protein was inversely correlated with the histopathological effect of inductive chemoradiotherapy; the rate of chemoradiotherapy-induced lethal degeneration (56.7%) in p53-negative SCCs was significantly higher than that (28.9%) in p53-positive SCCs (p < 0.005). However, no clear difference in the effect was observed between p21-positive and p21-negative SCCs. Finally, the 5-year-survival rate was highest in p53(-)-p21(+) (80.0%) followed by 76.3% in p53(-)-p21(-), 65.9% in p53(+)-p21(+) and 65.4% in p53(+)-21p(-) SCCs. These results indicate that although the expression of p21 protein is only weakly correlated with the clinico-histopathological findings, p53 protein is a useful prognostic marker and that inductive chemoradiotherapy can be successfully planned by immunohistochemical examination of p53 protein.
 ...
PMID:Expression of p53 and p21 proteins in oral squamous cell carcinoma: correlation with lymph node metastasis and response to chemoradiotherapy. 989 47

Induction of differentiation is today a useful strategy in cancer therapy but the clinical practice is insufficient in squamous cell carcinomas. We examined the effect of vesnarinone, a differentiation-inducing agent, on the cell cycle and cellular differentiation in four cell lines established from oral squamous cell carcinomas possessing a wild-type or mutated p53. Vesnarinone dose-dependently inhibited cell growth and induced G1 phase accumulation regardless of p53 gene mutation. The expression of involucrin and transglutaminase was increased by 4 days treatment with 60 microg/ml vesnarinone in all cell lines. Although p21 promoter activity was suppressed by vesnarinone, p21-mRNA was stabilized by the agent and expression of p21-mRNA was maintained for a long time. Corresponding to the prolonged p21-mRNA expression, p21 protein was induced by cell treatment with 60 microg/ml vesnarinone for 12 h and longer. The induced p21 protein bound cyclin E and suppressed cyclin E/Cdk2 kinase activity suppressing the phosphorylation of retinoblastoma (Rb) protein. These results suggest that vesnarinone possesses activity to induce p21 protein by stabilizing its mRNA with induction of differentiation of squamous cell carcinoma cells in a p53-independent manner.
 ...
PMID:Induction of cyclin-dependent kinase inhibitor p21 in vesnarinone-induced differentiation of squamous cell carcinoma cells. 992 58

Apoptosis-inducing therapy is becoming a new strategy in cancer therapy. We investigated the influence of 5-fluorouracil (5-FU) and radiation (gamma-ray) on the cell cycle of tumor cells, and their apoptosis-inducing activity using four oral squamous cell carcinoma lines (OSC-1 and OSC-4 with wild type p53; OSC-2 and OSC-3 with mutant type p53). The expression of p53 and cyclin-dependent kinase 2 (Cdk2) proteins was not increased even after cell treatment with 5-FU and gamma-rays in any cell lines. Although the promoter of p21 gene was not activated, p21-mRNA expression was increased by 5-FU and gamma-rays. p21 protein was expressed by irradiation in parallel with the increase in the messages but not by 5-FU in any OSC lines. Despite the increased p21 protein expression, cyclin E/Cdk2 kinase activity was not suppressed in irradiated cells. With the increased expression of cyclin E protein, 5-FU augmented the kinase activity in OSC-1, OSC-2 and OSC-3 cells. However, with a constant cyclin E level the kinase activity in OSC-4 was not increased by 5-FU. Without correlation to the kinase activity, 5-FU strongly induced apoptosis in OSC-2, OSC-3 and OSC-4 accumulating cells in the S phase, but 5-FU only very weakly induced apoptosis in OSC-1. While irradiated cells were in the G2/M phase, they exhibited apoptosis, to the same degree, in all OSC lines. Furthermore, the expression of Bax protein was not increased by 5-FU or gamma-rays, although apoptosis was induced by both treatments. These findings indicate that 5-FU and gamma-rays induce apoptosis of squamous cell carcinoma cells in p53- and p21-independent manners, in the S and G2/M phases, respectively.
 ...
PMID:p53- and p21-independent apoptosis of squamous cell carcinoma cells induced by 5-fluorouracil and radiation. 993 Mar 67

The cyclin-dependent kinase inhibitor p21waf1/Cip1 is a downstream effector of the p53-dependent cell growth arrest. We report herein that p21 was cleaved by caspase-3/CPP32 at the site of DHVD112L during the DNA damage-induced apoptosis of cancer cells. The cleaved p21 fragment could no more arrest the cells in G1 phase nor suppress the cells undergoing apoptosis because it failed to bind to the proliferating cell nuclear antigen (PCNA) and lost its capability to localize in the nucleus. Thus, caspase-3-mediated cleavage and inactivation of p21 protein may convert cancer cells from growth arrest to undergoing apoptosis, leading to the acceleration of chemotherapy-induced apoptotic process in cancer cells.
 ...
PMID:Caspase-mediated cleavage of p21Waf1/Cip1 converts cancer cells from growth arrest to undergoing apoptosis. 1002 18

p202 is an IFN-inducible, primarily nuclear, phosphoprotein (52-kDa) whose constitutive overexpression in transfected cells inhibits colony formation. To investigate the molecular mechanism(s) by which expression of p202 protein impairs colony formation, we established stable cell lines that inducibly express p202. Using this cell model, we demonstrate that the induced expression of p202 in asynchronous cultures of these cells was accompanied by: (a) an increase in steady-state levels of p21(WAF1/CIP1/SDI1) (p21) mRNA and protein; (b) a decrease in Cdk2 protein kinase activity; and (c) an increase in the functional form of retinoblastoma protein (pRb). Transient transfection of a p202-encoding plasmid in Saos-2 cells, which do not harbor a wild-type p53 protein, resulted in an increase in p21 protein, which indicated that p202 could regulate expression of p21 protein independent of p53 protein. Moreover, we demonstrate that expression of p202 in these cells increased cell doubling time without accumulation of cells in a particular phase of the cell cycle. Taken together, these results are consistent with the possibility that p202 protein contributes to the cell growth retardation activity of the IFNs, at least in part, by modulating p21 protein levels.
 ...
PMID:Retardation of cell proliferation after expression of p202 accompanies an increase in p21(WAF1/CIP1). 1007 3

It has been reported that p21, p53, and p16 affect the cell cycle and cell senescence. However, their roles in keratinocyte senescence are not clear. We established primary keratinocyte strains from 15 donors and maintained them until replicative senescence; their population doublings ranged from 5.7-45.2. These strains were classified based on their population doublings as short (5.7-10.4), intermediate (13.9-17.4), and long (21.5-45.2). To investigate the roles of p21, p53, and p16 in the cellular senescence of the cultured keratinocytes, we quantitatively analyzed p21, p53, and p16 levels of keratinocyte strains with different life spans by Western blot with Fluorol mager. p21 levels increased in the senescent phase but not in the nonsenescent phase in all of the short, intermediate, and long life-span strains. Northern blot analysis also revealed induction of p21 mRNA was similar to that of p21 protein levels. There were no apparent differences in p53 levels between senescent and nonsenescent cells. The short life-span strains exhibited a significant increase in p16 levels in the senescent phase (eighth or tenth passage). However, in two long life-span strains, p16 levels were increased in the nonsenescent phase (eighth passage) but then declined as the cells reached senescence (twenty-seventh passage). Therefore, induction of p16 appeared not to be associated with senescence in long life-span strains. In conclusion, p21 but not p16 or p53 may play roles in keratinocyte senescence.
 ...
PMID:Possible involvement of p21 but not of p16 or p53 in keratinocyte senescence. 1008 30

Quercetin, a widely distributed bioflavonoid, inhibited DNA synthesis in regenerating liver after partial hepatectomy. This inhibition was accompanied by apoptosis, evidenced by in situ end-labeling and gel electrophoresis of DNA fragmentation. Characteristic DNA fragmentation was detected as early as 2 h after injection. Northern blot analysis revealed that quercetin induced the increases in c-fos and p21WAF1CIP1 mRNA levels within 2 h. The expression of p21 protein was also enhanced, while p53 mRNA and protein levels were not affected by quercetin. These results suggest that quercetin-induced apoptosis is associated with the increase in c-fos mRNA level and the upregulation of p21 mRNA and protein expression, probably in a p53-independent pathway.
 ...
PMID:Quercetin inhibited DNA synthesis and induced apoptosis associated with increase in c-fos mRNA level and the upregulation of p21WAF1CIP1 mRNA and protein expression during liver regeneration after partial hepatectomy. 1008 92

Although polyamines are well recognized for their critical involvement in cell growth, the cell cycle specificity of this requirement has not yet been characterized with respect to the newly delineated regulatory pathways. We recently reported that polyamine analogues having close structural and functional similarities to the natural polyamines produce a distinct G1 and G2-M cell cycle arrest in MALME-3M human melanoma cells. To determine a molecular basis for this observation, we examined the effects of N1,N11-diethylnorspermine on cell cycle regulatory proteins associated with G1 arrest. The analogue is known to deplete polyamine pools by suppressing biosynthetic enzymes and potently inducing the polyamine catabolic enzyme spermidine/spermine N1-acetyltransferase. Treatment of MALME-3M cells with 10 microM N1,N11-diethylnorspermine caused an increase in hypophosphorylated Rb, which correlated temporally with the onset of G1 arrest at 16-24 h. Rb hypophosphorylation was preceded by an increase in wild-type p53 (approximately 100-fold at maximum) and a concomitant increase in the cyclin-dependent kinase inhibitor, p21WAF1/CIP1 (p21; approximately 5-fold at maximum). Another cyclin-dependent kinase inhibitor, p27KIP1, and cyclin D increased slightly, whereas proliferating cell nuclear antigen and p130 remained unchanged. Induction of p21 protein was accompanied by an increase in p21 mRNA, whereas induction of p53 protein was not, suggesting transcriptional activation of the former and posttranscriptional regulation of the latter. SK-MEL-28 human melanoma cells, which contain a mutated p53, failed to induce p53 or p21 and did not arrest in G1. Rather, these cells rapidly underwent programmed cell death within 48 h. Overall, these findings provide the first indication of the cell cycle regulatory pathways by which polyamine antagonists such as analogues might inhibit growth in cells containing wild-type p53 and further suggest a mechanistic basis for differential cellular responses to these agents.
 ...
PMID:Polyamine analogue induction of the p53-p21WAF1/CIP1-Rb pathway and G1 arrest in human melanoma cells. 1009 60


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>