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)

Human breast carcinoma MCF-7 cells seeded on type I collagen-coated dishes were provided with an anchor via the collagen receptor, integrin, and grew as actively as those in plastic tissue culture dishes. In contrast, cells seeded on a layer of soft agar became anchorage-deficient and their growth was significantly inhibited, although the cell viability and the cell cycle distribution were unaffected. Immunoprecipitation analysis revealed that mutant p53 was phosphorylated at tyrosine in the anchorage-provided cells. In contrast, the p53 in the anchorage-deficient cells was present in 2-fold greater amount, but was phosphorylated to a lesser extent. Addition of a potent protein-tyrosine kinase inhibitor, herbimycin A, to the anchorage-provided cells caused an elevated level of p53, and inhibitions of cell proliferation and p53 phosphorylation, without interfering with the cell adhesion to the substratum. These results demonstrated that the growth inhibition by anchorage-deficiency or by herbimycin A is associated with an elevated p53 level and reduced p53 phosphorylation at tyrosine.
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PMID:Growth inhibition by anchorage-deficiency is associated with increased level but reduced phosphorylation of mutant p53. 150 70

Immunostaining demonstrated that p53 protein was localized in the cytoplasm of growing MCF-7 cells and in the nuclei of cells that were growth arrested by serum starvation. Serum stimulation of the arrested cells induced marked increases in DNA synthesis and p53 phosphorylation, and translocation of the protein from the nucleus to the cytoplasm at 20 h after the stimulation. This increase in the DNA synthesis that was significantly inhibited by TGF-beta 1 was coincident with the inhibition of phosphorylation and cytoplasmic translocation of the p53 protein.
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PMID:Inhibition of DNA synthesis by TGF-beta 1 coincides with inhibition of phosphorylation and cytoplasmic translocation of p53 protein. 156 96

Mutations in the p53 gene are associated with a wide variety of human tumors, including those of the breast. To assess functionally the role of the p53 gene in the development of human breast cancer, we introduced either wild-type or mutant p53 cDNA into three human breast cancer cell lines by DNA transfection. The cell lines MDA-MB 468 and T47 D contain only single mutated copies of the p53 gene, whereas the status of p53 in the breast cancer cell line MCF 7 remains equivocal. Following transfection, MCF 7 cells continued to grow unaffected both in vitro and in vivo in the presence of high levels of expression of the exogenous wild-type p53 gene. In contrast, however, the continued expression of an exogenous wild-type p53 gene was incompatible with cellular growth in both the MDA-MB 468 and T47 D cell lines. Elevated levels of expression of the exogenous mutant p53 gene did not alter the growth of the cell lines in vitro. These data strongly suggest that the wild-type p53 gene can function as a suppressor of cellular growth in breast cancer cells. That the wild-type p53 gene does not suppress the growth of MCF 7 cells indicates that at least some human breast tumors can arise without functional inactivation of the p53 gene by mutation. These tumors may represent a separate prognostic group.
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PMID:Growth suppression of human breast cancer cells by the introduction of a wild-type p53 gene. 192 4

p53 messenger RNA expression was examined using a cDNA probe in 76 fresh primary breast tumour specimens, 15 of which came from patients treated with toxoxifen prior to surgery. A 2.8 kb mRNA for p53 was expressed in 43 of the 76 specimens. In 19 tumours the levels were similar to those seen in non-malignant (reduction mammoplasty) breast tissue, but in 24 tumours over-expression of mRNA for p53, approaching that seen in three breast cancer cell lines, was found. The cell lines MCF-7, T-47D and MDA-MB-231 expressed three p53 mRNA species of about 2.8 kb and a forth of 1.6 kb. Increased mRNA expression for p53 correlated (P less than 0.05) with loss of genetic material from the short arm of chromosome 17 as demonstrated by allele loss with the VNTR probe YNZ 22.1. There was also statistically significant correlation between increased p53 mRNA expression and low oestrogen receptor protein content in the tumours (P less than 0.05), but not with other clinical parameters. The findings support the view that p53 is involved in breast tumour biology, and suggest that its role may be complex.
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PMID:p53 gene mRNA expression and chromosome 17p allele loss in breast cancer. 213 9

Xenograft tumours from an oestrogen-dependent human breast cancer cell line MCF-7 have been established and characterised in thymectomised, irradiated female CBA strain mice. There was evidence for selection in xenografts of a subpopulation of MCF-7 cells with an altered pattern of gene expression as measured by mRNA levels compared with the original cells in vitro. Tumorigenicity increased significantly on repeated animal passage but oestrogen dependence was retained. Following injection of the mice with oestrogen, mitosis was induced in the tumour cells with associated increases in thymidine uptake and percentage of cells in S-phase. In accord with these changes, c-myc and p53 expression were increased and TGF-beta was suppressed. Thereafter the expression of the c-myc and p53 genes fell whilst that of the TGF-beta gene was induced as the oestrogenic-stimulus declined. The oestrogen-regulated mRNA pS2 showed a biphasic response to oestrogen and levels declined as the serum oestrogen fell to undetectable levels. This xenograft system demonstrates that changes in transcription of oncogenes, growth factor and oestrogen-regulated genes can be detected in vivo in response to oestrogen. It thus provides an in vivo model for studies of the biochemical and molecular basis for therapeutic manipulation of hormone-sensitive human breast cancer.
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PMID:Gene expression in oestrogen-dependent human breast cancer xenograft tumours. 239 Apr 87

The p21WAF1/CIP1 protein was shown to be a critical downstream effector of p53 and a potent inhibitor of cyclin-dependent kinases. We investigated the effects of exogenous p21WAF1/CIP1 in two different human breast carcinoma (HBC) cell lines MCF-7 and T47D. p21WAF1/CIP1 transfected cells formed significantly reduced number of drug-resistant colonies than their mock-transfected counterparts. The majority of the p21WAF1/CIP1 transfected MCF-7 cells acquired 50-100-fold increase in their sizes and persisted as single giant cells for several days without cell division, while the remainder underwent nuclear division (multiple nuclei) but were unable to complete cytokinesis, and finally all succumbed to apoptosis. Only few p21WAF1/CIP1 transfected T47D cells displayed increase in their sizes while a number of them formed small sized drug-resistant colonies which diminished in size due to cell death. The cells in these shrinking colonies exhibited characteristic signs of apoptosis such as chromatin condensation and fragmented nuclei while their membrane integrity was preserved. Thus in HBC cell lines the growth suppression due to enforced overexpression of p21WAF1/CIP1 is associated with giant cell formation and apoptosis.
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PMID:Overexpression of p21WAF1/CIP1 induces growth arrest, giant cell formation and apoptosis in human breast carcinoma cell lines. 747 20

p53 inhibits cell cycle progression and DNA damaging cytostatics induce p53 protein expression, indicating that p53 responds to DNA damage. We have measured benzo[a]pyrene (BP)-induced DNA damage in association with p53 expression. The most relevant DNA adducts for carcinogenesis, benzo[a]pyrene-7,8-diol-9,10-epoxide-DNA adducts, were measured by synchronous fluorescence spectrophotometry and p53 immunohistochemistry using polyclonal antibody CM1, which detects both wild-type and mutated forms of p53. Activation of BP in A-549 lung carcinoma and MCF-7 breast adenocarcinoma cell lines containing wild-type p53 was followed by an increase in p53 protein expression. alpha-Naphthoflavone, an inhibitor of cytochrome P450 (CYP)1A1, decreased both the formation of diolepoxide metabolites and the p53 response. The cell lines not able to activate BP, A-427 and SK-LU-1 (both human lung carcinomas), SK-MES-1 (human lung squamous carcinoma) and human fibroblasts, did not show any increase in p53 immunohistochemistry. The OVCAR-3 ovarian adenocarcinoma cell line, containing a mutation in exon 7 of p53, and the SK-LU-1 cell line expressed very high levels of p53 protein before BP treatment and no increase in p53 immunohistochemistry was seen. These findings indicate that p53 protein is part of the response of the cells to BP-induced DNA damage.
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PMID:p53 protein expression is correlated with benzo[a]pyrene-DNA adducts in carcinoma cell lines. 755 63

Protein kinase C (PKC) modulates growth, differentiation and apoptosis in a cell-specific fashion. Overexpression of PKC-alpha in MCF-7 breast cancer cells (MCF-7-PKC-alpha cell) leads to expression of a more transformed phenotype. The response of MCF-7 and MCF-7-PKC-alpha cells to phorbol esters (TPA) was examined. TPA-treated MCF-7 cells demonstrated a modest cytostatic response associated with a G1 arrest that was accompanied by Cip1 expression and retinoblastoma hypophosphorylation. While p53 was detected in MCF-7 cells, evidence for TPA-induced stimulation of p53 transcriptional activity was not evident. In contrast, TPA treatment induced death of MCF-7-PKC-alpha cells. Bryostatin 1, another PKC activator, exerted modest cytostatic effects on MCF-7 cells while producing a cytotoxic response at low doses in MCF-7-PKC-alpha cells that waned at higher concentrations. TPA-treated MCF-7-PKC-alpha cells accumulated in G2/M, did not express p53, displayed decreased Cip1 expression, and demonstrated a reduction in retinoblastoma hypophosphorylation. TPA-treated MCF-7-PKC-alpha cells expressed gadd-45 which occurred before the onset of apoptosis. Thus, alterations in the PKC pathway can modulate the decision of a breast cancer cell to undergo death or differentiation. In addition, these data show that PKC activation can induce expression of gadd45 in a p53-independent fashion.
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PMID:Phorbol esters induce death in MCF-7 breast cancer cells with altered expression of protein kinase C isoforms. Role for p53-independent induction of gadd-45 in initiating death. 756 79

Tumor necrosis factor-alpha (TNF-alpha) demonstrated antimitogenic activity in MCF-7 cells (estrogen receptor-positive human breast cancer cells) in a dose- and time-dependent manner (EC-50 of 2.5 ng/ml). This antimitogenic effect of TNF-alpha was accompanied by a decreased number of cells in S phase in a dose- and time-dependent manner. Based on growth arrest experiments using aphidicolin, it is apparent that TNF-alpha acted in early G1 phase. It did not show antimitogenic effects once cells reentered the S phase based on [3H]thymidine incorporation into DNA and cell cycle analysis. Specificity of TNF-alpha was established by using monoclonal anti-human TNF-alpha antibody. On the basis of Western immunoblot analysis of Rb, p53 and cell cycle inhibitory protein (Cip1) (p21) proteins, TNF-alpha decreased Rb protein expression in a dose- and time-dependent manner whereas it increased the expression level of tumor suppressor p53 protein. TNF-alpha also increased the expression level of Cip1 (p21) protein in a dose-dependent manner. This induction of Cip1 (p21) protein was preceded by the induction of p53 protein in MCF-7 cells. Cip1 (p21) protein associated with cyclin D was also increased. Tumor suppressor Rb protein expression was increased during G1 to S phase progression. Cyclin D protein expression levels were not changed in response to TNF-alpha treatment, although serine/threonine kinase inhibitors such as H7 and the protein kinase C inhibitor staurosporine decreased cyclin D expression levels in MCF-7 cells. Based on experiments with staurosporine, it appears that TNF-alpha does not utilize a protein kinase C pathway in MCF-7 cells. Other cell cycle-related proteins such as Cdk2, Cdc2, and Cdk4 did not show any change in response to TNF-alpha. TNF-alpha did not affect complexes between cyclin D and Cdk2, Cdk4, and Rb proteins in MCF-7 cells. Taken together these results suggest that Rb, p53, and Cip1 (p21) proteins mediate TNF-alpha antimitogenic activity, and TNF-alpha induces growth arrest in the G1 phase in MCF-7 cells.
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PMID:Effects of tumor necrosis factor-alpha on antimitogenicity and cell cycle-related proteins in MCF-7 cells. 762 60

The biological activity of a novel synthetic retinoid 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid (AHPN) was investigated in human breast carcinoma (HBC) cells. Although capable of selective binding to the RAR gamma nuclear receptor, AHPN inhibited the growth of a number of HBC cell lines via RAR- or RXR-independent pathways. AHPN also inhibited the growth of the human leukemia cell line HL-60R which does not possess functional RARs. RA significantly inhibited AP-1 mediated gene activation in MCF-7 cells while AHPN displayed no such anti-AP-1 activity. Retinoids normally are cytostatic in their inhibition of breast carcinoma growth and permit cell proliferation upon their removal, wher as AHPN induced G0/G1 arrest within 6h followed by apoptosis. In MCF-7 cells that harbor wild type p53, AHPN-induced G0/G1 arrest and apoptosis was accompanied by p53-independent regulation of WAF1/CIP1 as well as bax mRNA levels while bcl-2 mRNA levels were decreased. In MDA-MB-231 cells which possess a mutant p53, AHPN-mediated G0/G1 arrest and apoptosis was also associated with a concomitant up regulation of WAF1/CIP1 mRNA while these cells did not express bax or bcl-2 messages. Thus AHPN represents a novel retinoid that induces G0/G1 arrest and apoptosis via a unique pathway which appears to involve activation of known downstream effectors of p53 in a p53-independent manner.
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PMID:p53 independent G0/G1 arrest and apoptosis induced by a novel retinoid in human breast cancer cells. 763 Jun 33


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