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)

Previous studies have shown that induction of some genes by low-dose radiation has a different dependence on the time after irradiation than induction by high doses. To examine the mechanisms underlying this phenomenon, we investigated the changes in the time course of the rates of transcription of genes in cells of the human myeloblastic leukemia cell line ML-1 by a nuclear run-on assay. It is possible that the more rapid induction of the mRNA of the CDKN1A and GADD45 genes after exposure to 50 cGy of X rays than after 20 Gy is due to a lower level of stabilization of the mRNA of these genes after 50 cGy. In addition, our results show that 50 cGy of X rays increases the transcription rates of the CDKN1A and GADD45 genes, with a maximum induction at 0.5 to 1 h after irradiation, much earlier than the maximum accumulation of stabilized TP53 protein. We suggest the involvement of BRCA1 protein in the early induction of transcription of these two genes.
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PMID:Early induction of CDKN1A (p21) and GADD45 mRNA by a low dose of ionizing radiation is due to their dose-dependent post-transcriptional regulation. 1189 52

Mutations of the human breast cancer susceptibility gene 1 (BRCA1) confers a risk for breast, ovarian and prostate cancers and BRCA1 exerts multiple biological functions. Using Western blot and semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) assays, we have determined the expression of endogenous BRCA1 protein and mRNA in forty-three human tumor cell lines established from eleven types of human tumor tissues. BRCA1 was differentially expressed in tumor cell lines. No significant association was found between BRCA1 expression and the p53 gene status of cell lines. The disruption of wild-type p53 by either the human papillomavirus E6 oncogene or the mutant p53 gene (143Ala-->Val) did not cause any significant alteration in basal level of BRCA1 expression, while the knockout of p21 (-/-) by homologous recombination assay and Blocking Gadd45 expression by constitutive antisense expression slightly increased BRCA1 protein expression. Therefore, although the functional significance of the differential expression in human tumor cells is currently unknown, the present data provide a valuable background for further study of BRCA1 in tumor cell lines.
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PMID:BRCA1 is differentially expressed in human tumor cells. 1254 11

BRCA1 is a tumor suppressor gene that is responsible for hereditary breast and ovarian cancer syndrome. Increased evidence suggests that BRCA1 protein is involved in mammary carcinogenesis in sporadic and hereditary forms. Recent experimental results suggest that BRCA1 plays a role in the regulation of apoptosis. In order to test whether the analysis of human tumors would provide data supporting this hypothesis in sporadic breast carcinomas, we have investigated the relationship between BRCA1 and apoptosis-related genes. Immunohistochemical analysis was performed to determine BRCA1 and the apoptosis-related proteins bcl-2, Bax and p53 in paraffin-embedded tissues of 156 sporadic invasive ductal carcinomas. BRCA1 expression was positively-correlated with Bcl-2 expression (p = 0.0008), but no relationship between BRCA1 expression and Bax or p53 expression could be established. In addition, loss of BRCA1 expression was also related to poor tumor differentiation and lymph node metastasis. Our study shows that bcl-2 might be one of the target genes involved in the oncogenesis related to BRCA1. Loss of BRCA1 may contribute to tumor development in breast carcinomas, which may be independent of the p53 tumor suppressor.
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PMID:Correlation between BRCA1 expression and apoptosis-related biological parameters in sporadic breast carcinomas. 1255 65

A human tumor xenograft (L56Br-X1) was established from a breast cancer axillary lymph node metastasis of a 53-year-old woman with a BRCA1 germ-line nonsense mutation (1806C>T; Q563X), and a cell line (L56Br-C1) was subsequently derived from the xenograft. The xenograft carries only the mutant BRCA1 allele and expresses mutant BRCA1 mRNA but no BRCA1 protein as determined by immunoprecipitation or Western blotting. The primary tumor, lymph node metastasis, and xenograft were hypodiploid by DNA flow cytometry, whereas the cell line displayed an aneuploidy apparently developed via polyploidization. Cytogenetic analysis, spectral karyotyping, and comparative genomic hybridization of the cell line revealed a highly complex karyotype with numerous unbalanced translocations. The xenograft and cell line had retained a somatic TP53 missense mutation (S215I) originating from the primary tumors, as well as a lack of immunohistochemically detectable expression of steroid hormone receptors, epidermal growth factor receptor, human epidermal growth factor receptor 2 (HER-2), and keratin 8. Global gene expression analysis by cDNA microarrays supported a correlation between the expression profiles of the primary tumor, lymph node metastasis, xenograft, and cell line. We conclude that L56Br-X1 and L56Br-C1 are useful model systems for studies of the pathogenesis and new therapeutic modalities of BRCA1-induced human breast cancer.
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PMID:Characterization of a novel breast carcinoma xenograft and cell line derived from a BRCA1 germ-line mutation carrier. 1264 39

BRCA1 is a tumor suppressor gene linked to familial breast and ovarian cancer. The BRCA1 protein has been implicated in a diverse set of cellular functions, including activation of gene expression by the p53 tumor suppressor and control of homologous recombination (HR) during DNA repair. Prior reports have demonstrated that BRCA1 can exist in cells in a complex with the BRG1-based SWI/SNF ATP-dependent chromatin remodeling enzymes and that SWI/SNF components contribute to p53-mediated gene activation. To investigate the link between SWI/SNF function and BRCA1 mediated effects on p53-mediated gene activation and on mechanisms of homologous recombination, we have utilized mammalian cells that inducibly express an ATPase-deficient, dominant negative SWI/SNF enzymes. Mutant SWI/SNF ATPases retain the ability to interact with BRCA1 in cells. We report that expression of dominant negative SWI/SNF enzymes does not affect p53-mediated induction of the p21 cyclin dependent kinase inhibitor or the Mdm2 E3 ubiquitin ligase that regulates p53 in cells exposed to UV or gamma irradiation. Similarly, integration of a reporter that monitors homologous recombination by gene conversion into these cells demonstrated no change in the recombination rate in the absence of functional SWI/SNF enzyme. We conclude that the SWI/SNF chromatin remodeling enzymes may contribute to but are not required for these processes.
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PMID:BRCA1 interacts with dominant negative SWI/SNF enzymes without affecting homologous recombination or radiation-induced gene activation of p21 or Mdm2. 1503 33

The tumor suppressor gene BRCA1 plays an important role in the response to DNA damage. BRCA1 function is regulated by a variety of mechanisms including transcriptional control, phosphorylation, and protein-protein interactions. Recent studies have shown that BRCA1 is a nuclear-cytoplasmic shuttle protein. Its subcellular localization is controlled by a nuclear localization signal-mediated nuclear import via the importin receptor pathway and a nuclear export signal-facilitated nuclear export through a CRM1-dependent pathway. Using the human breast cancer cell line, MCF7, the subcellular distribution of BRCA1 was assessed by immunohistochemical staining and Western blotting analyses of fractionated subcellullar extracts. Ionizing radiation stimulated BRCA1 nuclear export in a dose-dependent manner. This DNA damage-induced BRCA1 nuclear export utilized a CRM1-dependent mechanism and also required wild-type p53, whose function was abrogated by the E6 protein in MCF7 cells. In addition, the dependence on p53 was confirmed using a second cell type operating a tetracycline-inducible system. The effect of ionizing radiation on BRCA1 export was observed in every phase of the cell cycle, although BRCA1 localization did vary between the G(1), S, and G(2)/M phases. These results imply that, in addition to ATM-, ATR-, and Chk2-dependent phosphorylations, cytoplasmic relocalization of BRCA1 protein is a mechanism whereby BRCA1 function is regulated in response to DNA damage.
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PMID:DNA damage induces p53-dependent BRCA1 nuclear export. 1508 57

BRCA1 is a large protein that exhibits a multiplicity of functions in its apparent role in DNA repair. Certain mutations of BRCA1 are known to have exceptionally high penetrance with respect to familial breast and ovarian cancers. The structures of the N-terminus and C-terminus of the protein have been determined. The C-terminus unit consists of two alpha-beta-alpha domains designated BRCT. We predicated two homologous BRCT regions in the BRCA1 internal region, and subsequently produced and purified these protein domains. Both recombinant domains show significant self-association capabilities as well as a preferential tendency to interact with each other. These results suggest a possible regulatory mechanism for BRCA1 function. We have demonstrated p53-binding activity by an additional region, and confirmed previous results showing that two regions of BRCA1 protein bind p53 in vitro. Based on sequence analysis, we predict five p53-binding sites. Our comparison of binding by wild-type and mutant domains indicates the sequence specificity of BRCA1-p53 interaction.
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PMID:Primary structure-based function characterization of BRCT domain replicates in BRCA1. 1667 9

The role of caveolae and the caveolin proteins in cancer has been the subject of extensive research. BRCA1 participates in multiple biological pathways including DNA damage repair, transcriptional control, cell growth, apoptosis, and others. Little information, however, is available regarding the cellular mechanisms that control BRCA1 gene expression. The present study examined the potential regulation of BRCA1 gene expression and subcellular localization by Cav-1. Results of Western blots, RT-PCR, and transfection experiments showed that Cav-1 enhances BRCA1 protein and mRNA levels via a mechanism that involves transactivation of the BRCA1 promoter and which is p53-dependent. In addition, immunostaining experiments demonstrate that Cav-1 induced the cytoplasmic sequestration of BRCA1.
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PMID:Caveolin-1 controls BRCA1 gene expression and cellular localization in human breast cancer cells. 1697 66

Women with mutations in the breast cancer susceptibility gene BRCA1 are predisposed to breast and ovarian cancers. Why the BRCA1 protein suppresses tumor development specifically in ovarian hormone-sensitive tissues remains unclear. We demonstrate that mammary glands of nulliparous Brca1/p53-deficient mice accumulate lateral branches and undergo extensive alveologenesis, a phenotype that occurs only during pregnancy in wild-type mice. Progesterone receptors, but not estrogen receptors, are overexpressed in the mutant mammary epithelial cells because of a defect in their degradation by the proteasome pathway. Treatment of Brca1/p53-deficient mice with the progesterone antagonist mifepristone (RU 486) prevented mammary tumorigenesis. These findings reveal a tissue-specific function for the BRCA1 protein and raise the possibility that antiprogesterone treatment may be useful for breast cancer prevention in individuals with BRCA1 mutations.
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PMID:Prevention of Brca1-mediated mammary tumorigenesis in mice by a progesterone antagonist. 1713 73

IFI16 is a member of the HIN-200 family (hematopoietic interferon-inducible nuclear antigens with 200 amino acid repeat) that contains a DNA binding domain, a transcriptional regulatory domain, DAPIN/PAAD domain associated with interferon (IFN) response and a binding domain for BRCA1, breast cancer tumor suppressor protein. IFI16 has been identified as a target of IFNa and g and is a member of the HIN-200 family. Although series of initial studies have demonstrated a potential activity of IFI16, a physiological role of the protein was largely unknown. A novel insight of the function of IFI16 stemmed from the observation that IFI16 constitutively binds to BRCA1 breast cancer tumor suppressor. Furthermore, it has been demonstrated that IFI16 is involved in p53-mediated regulation of cell growth and apoptosis. Immunocytochemical and immunohistological analyses of breast cancer cell lines and specimens revealed that levels of IFI16 are frequently decreased, supporting the notion that loss of IFI16 is closely associated with tumor development. Finally, siRNA-mediated depletion of IFI16 induces levels of NBS1, nijmegen breakage syndrome protein 1, leading to activation of DNA-PK (DNA-dependent kinase), phosphorylation of p53 Ser37 and accumulation of p21WAF1. Localization of IFI16 is determined by the status of BRCA1 protein under conditions of DNA damage, such as ionizing radiation (IR). More recently, it has been shown that levels of IFI16 are increased by oxidative stress. Together, these results illustrate that IFI16 is involved in DNA damage signaling and cell cycle checkpoint.
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PMID:Role of IFI16 in DNA damage and checkpoint. 1798 41


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