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)

Recent evidence from our laboratory suggests that the fraction of cells with lethal mutations is lost from the population by apoptosis. The relationship of this process to genetic instability and carcinogenesis is unclear. To examine this, tumorigenic cell populations derived from spontaneously occurring, neoplastically transformed C3H 1OT1/2 foci and from radiation-induced foci were compared with wild-type C3H 10T1/2 cell populations to determine the frequency of induction of lethal mutations postirradiation. Lethal mutations did not occur in the progeny of cells from type 3 foci derived from cultures of spontaneously occurring or radiation-induced neoplastically transformed cells but were very frequent in the progeny of irradiated wild-type cells. Normal human cells (HPV-immortalized human keratinocytes and primary human normal uroepithelium) were then treated with carcinogens or transfected with the Ha-ras oncogene to see if these carcinogenic events affected the yield of lethal mutations postirradiation. In each case, cells which were exposed to a carcinogenic agent had reduced numbers of lethal mutations, elevated levels of stable p53 and Bcl-2 proteins and reduced evidence of apoptosis. It is suggested that lethal mutations may represent an active safety mechanism which may deal with radiation-induced genomic instability and which is disabled early in carcinogenesis.
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PMID:Expression of lethal mutations is suppressed in neoplastically transformed cells and after treatment of normal cells with carcinogens. 864 31

The Bcl-2 protein coded by the proto-oncogene bcl-2 is expressed in a variety of embryonic and postnatal tissues and is overproduced in several types of tumours. Bcl-2 expression suppresses apoptosis induced by a multitude of stimuli in diverse cell types without exerting significant effects on cell proliferation, and is believed to contribute to oncogenesis by extending cell survival. In certain B-cell lymphomas, chromosomal translocations result in a gain of function of Bcl-2 by overexpression. Here, we report that a deletion of a nonconserved region of human Bcl-2 (residues 51-85) confers a novel gain of function that not only suppresses apoptosis induced by the tumor suppressor protein p53 and the Myc oncoprotein but also permits continued cell proliferation. Our result raises the possibility that mutations within the bcl-2 gene may contribute to oncogenesis by both suppressing apoptosis and facilitating cell proliferation.
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PMID:Deletion of a nonconserved region of Bcl-2 confers a novel gain of function: suppression of apoptosis with concomitant cell proliferation. 865 86

The endogenous expression of p53 and p53-regulated genes has been examined in a thymidylate synthase-deficient colon carcinoma cell line (TS-) and a derived mutant clone (Thy4) that exhibit acute or delayed apoptotic responses, respectively, when released from G0 synchrony under conditions of dThd starvation. These cell clones demonstrate heterozygosity in p53, thereby expressing one wt allele and one with an A-->C point mutation at codon 240. Following release from G0, upregulated expression of both alleles occurred. During apoptosis in TS-, a wtp53 phenotype was expressed and in Thy4 during cytostasis, a mp53 phenotype was manifested, as determined from the ratios of wtp53/mp53 proteins, transactivation of p50-2 (a wtp53-responsive CAT reporter construct) and the endogenous expression of MDM2. Neither cytotoxicity nor cytostasis correlated with expression of p21Waf1/Cip1 Thy4 cells sustained accumulation of high levels of Bax in a wtp53-independent and dThd-independent manner and survival was associated with upregulated expression of Bcl-2. In contrast, Bax expression decreased in TS- during apoptosis, except in a highly resistant subpopulation that retained high levels of Bax. Data suggest that resistant cells (Thy4) can sustain high Bax expression and that Bcl-2 is upregulated in response to an apoptotic stimulus due to the absence of negative regulation by wtp53.
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PMID:Acute and delayed apoptosis induced by thymidine deprivation correlates with expression of p53 and p53-regulated genes in colon carcinoma cells. 866 31

We investigated expression of Bcl-2, mutations in p53, and K-ras oncogene in 51 resected human non-small cell lung cancers. The studies were designed to test for the possibility of cooperativity between these oncogenes and p53 in the pathogenesis of lung cancer. An inverse relationship was found between expression of Bcl-2 and mutant p53 by immunohistochemistry (P < 0.01; Fisher exact test), suggesting that either Bcl-2 overexpression or mutations in p53 may fulfill a critical function in the pathogenesis of human non-small cell lung cancers. Tumors that harbored K-ras codon 12 mutations seldom had p53 mutations or overexpressed Bcl-2. Statistical analysis of these data showed that mutations in p53 and K-ras or overexpression of Bcl-2 and mutations in K-ras occurred at a frequency that could be explained only by chance [P > 0.1 in each case (Fisher exact tests)]. This suggests that cooperativity between mutant K-ras and mutant p53 or mutant K-ras and overexpressed Bcl-2 is not a common mechanism in the pathogenesis of human non-small cell lung cancers.
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PMID:Overexpression of Bcl-2 and mutations in p53 and K-ras in resected human non-small cell lung cancers. 867 21

The aim of this study was to assess relationships between Bcl-2 expression, response to chemotherapy and a number of pathological and biological tumour parameters in premenopausal, lymph node-negative breast cancer patients. Expression of Bcl-2 was determined using immunohistochemistry on paraffin-embedded sections in a series of 441 premenopausal, lymph node-negative breast cancers of patients randomised to receive perioperative chemotherapy (5-fluorouracil, doxorubicin, cyclophosphamide) or no perioperative chemotherapy. Immunohistochemistry of Bcl-2 was evaluated by scoring both staining intensity (0-3) and number of positive cells (0-2). Using these scores tumours were grouped into categories 0-6. It was found that 9.2% of the tumours were completely negative (0), 17.2% weakly (1 + 2), 41.6% moderately (3 + 4) and 31.9% strongly positive (5 + 6) for Bcl-2. A positive correlation was found between high Bcl-2 expression and oestrogen (P < 0.001) and progesterone receptor positivity (P < 0.001) and low tumour grade (P < 0.001), whereas high Bcl-2 expression was negatively correlated with p53 (P < 0.001) and c-erb-B-2 positively (P < 0.001), high Ki-67 index (P < 0.001), mitotic index (P < 0.001) and large tumour size (P = 0.006). Patients with tumours expressing high levels of Bcl-2 (overall score 3-6) had a significantly better disease-free (P = 0.004) and overall (P = 0.009) survival. However, in a multivariate model this association no longer remained significant. There was a trend for an effect of adjuvant chemotherapy on disease-free survival both for patients with Bcl-2-positive (HR-0.61, 95% CI 0.35-1.06, P = 0.07) and negative (HR = 0.55, 95% CI 0.27-1.12, P = 0.09) breast tumours at a median follow-up of 49 months. The level of Bcl-2 expression does not seem to predict response to perioperative chemotherapy in premenopausal, lymph node-negative breast cancer patients. High levels of Bcl-2 are preferentially expressed in well-differentiated tumours and are associated with favourable prognosis. However, Bcl-2 expression is not an independent prognostic factor in this patient series.
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PMID:Expression of Bcl-2 in node-negative breast cancer is associated with various prognostic factors, but does not predict response to one course of perioperative chemotherapy. 867 63

Tests for estrogen (ER) and progesterone (PR) receptors, c-erbB-2, p53 and Bcl-2 were made on paraffin sections of thirty-three cases of invasive micropapillary carcinoma (MPCa) of the breast. The relations between these proteins and general parameters and the patients' evolution, were analyzed and their statistical significance determined by Fisher's exact test. Follow up was available on twenty one patients of whom thirteen were alive after a mean of sixty months. Tumor size, metastatic nodes, c-erbB-2 and Bcl-2 all showed higher values in the dead patient group, but only nuclear grade and extensive lymphatic vessel invasion (LVI) were statistically significant prognostic factors. Hormone receptors and oncogenes were positive in quite similar figures to those of common breast cancers (NOSCa) and offered supplementary information about differentiation and cell atypia of individual cancers. Accordingly, ER (72.7%), PR (45.4%) and Bcl-2 (69.6%) were directly interrelated and inversely related with nuclear grade, mitotic grade, c-erbB-2 (36.3%) and p53 (12.1%). In conclusion, MPCa is a lymphotropic cancer phenotype whose prognosis can be influenced by known prognostic factors, including molecular. The lack of discriminative power between MPCa and NOSCa of ER, PR, c-erbB-2, p53, and Bcl-2 reinforces the importance of recognizing this particular type of cancer.
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PMID:Estrogen and progesterone receptors, c-erbB-2, p53, and Bcl-2 in thirty-three invasive micropapillary breast carcinomas. 868 38

The expression of the apoptosis-regulating genes Bcl-2, Bcl-x, Bax, Mcl-1, and p53 analyzed in 4 cases of human immunodeficiency virus (HIV)-associated Hodgkin's disease, in 36 cases of HIV-related non-Hodgkin's lymphomas (NHLs), and in 109 cases of non-HIV-related NHLs by using immunohistochemistry. HIV-associated Hodgkin's disease samples were positive for all markers. For the HIV-related NHL samples, 36, 66, 88, 100, and 94% of the cases were Bcl-2, Bcl-x, Bax, Mcl-1, and p53 were found to be expressed in 69, 65, 82, 83, and 42%, respectively. No significant differences were observed in Bax and Mcl-1 staining between HIV-unrelated NHLs of B cell and T cell types. In contrast, Bcl-2 was positive in 66/79 (83%) and 10/30 (33%) of B cell and T cell HIV-unrelated NHLs, respectively (P2 < 0.001). Peculiar patterns were observed for hairy cell leukemia (Bax+, Bcl-2+, Mcl-1-) and for anaplastic large cell lymphoma (Bax+, Mcl-1+, Bcl-2-) in HIV-unrelated NHLs. Of interest, all cases with a positive expression of Bax were also found to express either Mcl-1 and/or Bcl-2, suggesting that Mcl-1 and Bcl-2 may counteract the pro-apoptosis function of Bax in vivo by protein-protein interaction within the tumor cell, as demonstrated previously in vitro. These results suggest that apoptosis regulation may have a role in the pathogenesis of some HIV-related and HIV-unrelated NHLs.
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PMID:Immunodetection of apoptosis-regulating proteins in lymphomas from patients with and without human immunodeficiency virus infection. 868 41

Recent advances in molecular biology have revealed various genetic lesions in lung cancer. Mutations of the K-ras gene, amplification or overexpression of myc family genes, erbB2 gene, or bcl2 gene are frequent genetic changes of oncogenes in lung cancer. Inactivation of tumor suppressor genes such as Rb gene, p53 gene, or p16 gene are also seen rather frequently. Furthermore, loss of heterozygosity at certain chromosomal arms such as 3p, 5q, 18q and 22q suggesting inactivation of yet unidentified tumor suppressor genes, also occurs in a significant proportion of lung cancers. Most of these genetic lesions have been reported to be associated with a poor prognostic outcome of the patients. However, great controversy exists as to whether a certain genetic lesion is really a prognostic marker. For example, although about 20 studies have been published, the prognostic implications of the p53 gene for patients with lung cancer still remain unclear. Little is known about the mechanism through which a certain genetic change affects the patient's prognosis. To ultimately improve the prognosis of patients with this deadly disease, definitive studies on which subsequent clinical trials can rely are much awaited.
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PMID:[Genetic abnormalities in lung cancer and their prognostic implications]. 868 34

We review some of the most recent developments concerning three genes involved in human cancer: p53, bcl2 and c-myc. Recent data have demonstrated that the bcl2 gene protects tumor cells from apoptosis induced by a variety of agents, including ionizing radiation, and is thus related to resistance to DNA-damaging therapeutic agents. The p53 tumor suppressor gene, however, has been related with growth arrest, apoptosis and thus with selective sensitivity to the killing effects of ionizing radiation and DNA-damaging drugs. This functional antagonism between the two genes was recently substantiated in molecular terms by demonstration of reciprocal down-regulation due to the presence of a p53-dependent transcription silencer in the untranslated region of the bcl2 gene. Growth arrest in the G1 phase of the cell cycle and induction of apoptosis are two distinct and dissectable functions of p53: bcl2 is able to antagonize the induction of apoptosis by p53, but not the growth arrest in G1. However, coexpression of bcl2 and of the oncogene c-myc efficiently antagonizes effects of p53 on G1 arrest and apoptosis, thus suggesting a cooperation between the two oncogenes. In addition, c-myc disrupts other functions of genetic control in the early G1 phase of the cell cycle including the expression of D1 cyclin. We believe that knowledge of the functional/molecular interactions between these three genes involved in human cancer is a fundamental prerequisite to improve the knowledge on prognosis and to design innovative therapeutic approaches.
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PMID:Role of three cancer "master genes" p53, bcl2 and c-myc on the apoptotic process. 869 93

Among the many target genes of the transcription factor NF-kappaB are p53 and c-myc, both of which are involved in apoptosis. This prompted us to investigate the role of NF-kappaB in this process. We report that NF-kappaB is potently activated upon serum starvation, a condition leading to apoptosis in 293 cells. Similar to Bcl-2, a transdominant-negative mutant of the NF-kappaB p65 subunit partially inhibited apoptosis, indicating a direct involvement of the transcription factor in induction of cell death. As expected, the p65 mutant suppresses kappaB-dependent gene expression. Surprisingly, transiently or stably overexpressed Bcl-2 had the same effect. The transcription inhibitory activity of the two proteins correlated with their cell death protective potential. Like Bcl-2, the related protein Bcl-xL but not Bcl-xS was able to suppress kB-dependent transcription. Bcl-2 inhibited NF-kappaB activity by an unusual mechanism. It did not prevent the release of IkappaB in the cytoplasm but down-modulated the transactivating potential of nuclear p65. These data show that NF-kappaB can participate in apoptosis. We suggest that at least part of the anti-apoptotic potential of Bcl-2 may be explained from a hitherto undiscovered activity of Bcl-2 in controlling nuclear gene expression.
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PMID:Bcl-2 down-regulates the activity of transcription factor NF-kappaB induced upon apoptosis. 869 9


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