Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

BRCA1 has been implicated in the transcriptional regulation of DNA damage-inducible genes that function in cell cycle arrest. To explore the mechanistic basis for this regulation, a novel human gene, ZBRK1, which encodes a 60 kDa protein with an N-terminal KRAB domain and eight central zinc fingers, was identified by virtue of its interaction with BRCA1 in vitro and in vivo. ZBRK1 binds to a specific sequence, GGGxxx CAGxxxTTT, within GADD45 intron 3 that supports the assembly of a nuclear complex minimally containing both ZBRK1 and BRCA1. ZBRK1 represses transcription through this recognition sequence in a BRCA1-dependent manner. These results thus reveal a novel corepressor function for BRCA1 and provide a mechanistic basis for the biological activity of BRCA1 through sequence-specific transcriptional regulation.
Mol Cell 2000 Oct
PMID:Sequence-specific transcriptional corepressor function for BRCA1 through a novel zinc finger protein, ZBRK1. 1109 Jun 15

Germline mutations in the breast and ovarian cancer susceptibility gene BRCA1 are responsible for the majority of cases involving hereditary breast and ovarian cancer. Whereas all truncating mutations are considered as functionally deleterious, most of the missense variants identified to date cannot be readily distinguished as either disease-associated mutations or benign polymorphisms. The C-terminal domain of BRCA1 displays an intrinsic transactivation activity, and mutations linked to disease predisposition have been shown to confer loss of such activity in yeast and mammalian cells. In an attempt to clarify the functional importance of the BRCA1 C-terminus as a transcription activator in cancer predisposition, we have characterized the effect of C-terminal germline variants identified in Scandinavian breast and ovarian cancer families. Missense variants A1669S, C1697R, R1699W, R1699Q, A1708E, S1715R and G1738E and a truncating mutation, W1837X, were characterized using yeast- and mammalian-based transcription assays. In addition, four additional missense variants (V1665M, D1692N, S1715N and D1733G) and one in-frame deletion (V1688del) were included in the study. Our findings demonstrate that transactivation activity may reflect a tumor-suppressing function of BRCA1 and further support the role of BRCA1 missense mutations in disease predisposition. We also report a discrepancy between results from yeast- and mammalian-based assays, indicating that it may not be possible to unambiguously characterize variants with the yeast assay alone. We show that transcription-based assays can aid in the characterization of deleterious mutations in the C-terminal part of BRCA1 and may form the basis of a functional assay.
Hum Mol Genet 2001 Feb 15
PMID:Functional analysis of BRCA1 C-terminal missense mutations identified in breast and ovarian cancer families. 1115 98

A novel approach to mutation screening in the large exon 11 (comprising 3427 bp) of the human BRCA1 gene is presented. Restriction endonuclease fingerprinting single-strand conformation polymorphism (REF-SSCP) is based on repeated detection of DNA sequence variants in different restriction endonuclease fragments, and we evaluated the method using blood samples from 25 Norwegian patients with hereditary breast/ovarian cancer. We compared REF-SSCP to constant denaturant gel electrophoresis (CDGE) and to the protein truncation test (PTT). REF-SSCP detected 12 different DNA variants. Four of these were not detected by CDGE, and only one variant detected by CDGE was missed by REF-SSCP. PTT detected 4 of these 13 variants. REF-SSCP was subsequently applied to a second patient series (Swedish, n=20). A total of 14 different DNA variants were detected by REF-SSCP, 6 of which were truncating mutations (PTT detected only 4). Nonsense and frameshift mutations that are putative breast/ovarian cancer mutations, were detected in 7 of the 25 Norwegian and 9 of the 20 Swedish patients.
J Mol Med (Berl) 2000
PMID:Enhanced detection of mutations in BRCA1 exon 11 using restriction endonuclease fingerprinting-single-strand conformation polymorphism. 1119 32

Fanconi anemia (FA) is a human autosomal recessive cancer susceptibility disorder characterized by cellular sensitivity to mitomycin C and ionizing radiation. Although six FA genes (for subtypes A, C, D2, E, F, and G) have been cloned, their relationship to DNA repair remains unknown. In the current study, we show that a nuclear complex containing the FANCA, FANCC, FANCF, and FANCG proteins is required for the activation of the FANCD2 protein to a monoubiquitinated isoform. In normal (non-FA) cells, FANCD2 is monoubiquitinated in response to DNA damage and is targeted to nuclear foci (dots). Activated FANCD2 protein colocalizes with the breast cancer susceptibility protein, BRCA1, in ionizing radiation-induced foci and in synaptonemal complexes of meiotic chromosomes. The FANCD2 protein, therefore, provides the missing link between the FA protein complex and the cellular BRCA1 repair machinery. Disruption of this pathway results in the cellular and clinical phenotype common to all FA subtypes.
Mol Cell 2001 Feb
PMID:Interaction of the Fanconi anemia proteins and BRCA1 in a common pathway. 1123 54

Germline mutations in the tumor suppressor genes BRCA1 and BRCA2 predispose individuals to breast and ovarian cancers. Progress in determining the function of BRCA1 and BRCA2 suggests that they are involved in two fundamental cellular processes: DNA damage repair and transcriptional regulation. We evaluate current knowledge of BRCA1 and BRCA2 functions to explain why mutations in BRCA1 and BRCA2 lead specifically to breast and ovarian cancer. The BRCA1 and BRCA2 genes contain unusually high densities of repetitive elements. These features of the BRCAs genomic regions contribute to chromosomal instability of these genes. We propose that somatic alterations of BRCA1 and BRCA2 are common and driven by rearrangements between repetitive elements. Inherited and somatic mutations occur in BRCA1 and BRCA2; virtually all somatic mutations are the result of large genomic rearrangements. What are the consequences of such large somatic mutations of BRCA1 and BRCA2 in women with or without inherited mutations? The breast and ovary are estrogen-responsive tissues. Beginning in puberty, the breast epithelium proliferates rapidly in response to fluctuating levels of estrogen. We present a genetic model outlining how BRCA-deficient cells may gain uncontrolled proliferation leading to tumor formation. Central to this model of BRCA-mediated tumorigenesis are estrogen-mediated proliferation of breast and ovarian epithelium and the distinctive genomic context of the BRCA genes.
Hum Mol Genet 2001 Apr
PMID:BRCA1 and BRCA2 and the genetics of breast and ovarian cancer. 1125 3

While germline mutations in BRCA1 and BRCA2 account for most, if not all families with autosomal dominant transmission of susceptibility to both breast and ovarian cancer, it has become clear that together these genes only account for a small proportion of hereditary site-specific breast cancer susceptibility. However, difficulties due to genetic heterogeneity, reduced penetrance and perhaps gene mutation frequency complicate ongoing efforts to identify additional susceptibility genes. Therefore, multiple approaches are being used to identify additional high and low penetrance genes. Families with three or more breast cancer cases are being used in traditional linkage studies, which are expected to yield only moderate or high penetrance susceptibility genes. Breast cancer case-control studies are being used to look for genetic variants or polymorphisms that confer an increased risk of breast cancer in a wide variety of cellular pathways, ranging from the detoxification of environmental carcinogens to steroid hormone metabolism, DNA damage repair and immune surveillance, an approach useful primarily to identify low penetrance susceptibililty genes. However, neither approach has yielded convincing results to date. A third approach, using BRCA1 and BRCA2 mutation carriers to identify genes that are associated with modification of breast cancer risk has met with some limited success, perhaps because effects on breast cancer risk in BRCA1 and BRCA2 mutation carriers are more readily detected in smaller studies, given the much higher number of events in these cohorts at very high risk of breast cancer. Clearly, hereditary breast cancer susceptibility is a complex phenomenon, in which multiple genes may play a role. It will be necessary to use all of these approaches, as well as more comprehensive genomic studies, to identify additional breast cancer-related genes.
Hum Mol Genet 2001 Apr
PMID:"Other" breast cancer susceptibility genes: searching for more holy grail. 1125 4

Deficiency in a helicase of the RecQ family is found in at least three human genetic disorders associated with cancer predisposition and/or premature ageing. The RecQ helicases encoded by the BLM, WRN and RECQ4 genes are defective in Bloom's, Werner's and Rothmund-Thomson syndromes, respectively. Cells derived from individuals with these disorders in each case show inherent genomic instability. Recent studies have demonstrated direct interactions between these RecQ helicases and human nuclear proteins required for several aspects of chromosome maintenance, including p53, BRCA1, topoisomerase III, replication protein A and DNA polymerase delta. Here, we review this network of protein interactions, and the clues that they present regarding the potential roles of RecQ family members in DNA repair, replication and/or recombination pathways.
Hum Mol Genet 2001 Apr
PMID:DNA helicase deficiencies associated with cancer predisposition and premature ageing disorders. 1125 7

The order Rodentia contains half of all extant mammal species, and from an evolutionary standpoint, there are persistent controversies surrounding the monophyly of the order, divergence dates for major lineages, and relationships among families. Exons of growth hormone receptor (GHR) and breast cancer susceptibility (BRCA1) genes were sequenced for a wide diversity of rodents and other mammals and combined with sequences of the mitochondrial 12S rRNA gene and previously published sequences of von Willebrand factor (vWF). Rodents exhibit rates of amino acid replacement twice those observed for nonrodents, and this rapid rate of evolution influences estimates of divergence dates. Based on GHR sequences, monophyly is supported, with the estimated divergence between hystricognaths and most sciurognaths dating to about 75 MYA. Most estimated dates of divergence are consistent with the fossil record, including a date of 23 MYA for Mus-Rattus divergence. These dates are considerably later than those derived from some other molecular studies. Among combined and separate analyses of the various gene sequences, moderate to strong support was found for several clades. GHR appears to have greater resolving power than do 12S or vWF. Despite its complete unresponsiveness to growth hormone, Cavia (and other hystricognaths) exhibits a conservative rate of change in the intracellular domain of GHR.
Mol Biol Evol 2001 May
PMID:Molecular phylogeny and divergence time estimates for major rodent groups: evidence from multiple genes. 1131 62

Transforming growth factor beta (TGFbeta) signaling is transduced via Smad2-Smad4-DNA-binding protein complexes which bind to responsive elements in the promoters of target genes. However, the mechanism of how the complexes activate the target genes is unclear. Here we identify Xenopus Swift, a novel nuclear BRCT (BRCA1 C-terminal) domain protein that physically interacts with Smad2 via its BRCT domains. We examine the activity of Swift in relation to gene activation in Xenopus embryos. Swift mRNA has an expression pattern similar to that of Smad2. Swift has intrinsic transactivation activity and activates target gene transcription in a TGFbeta-Smad2-dependent manner. Inhibition of Swift activity results in the suppression of TGFbeta-induced gene transcription and defective mesendoderm development. Blocking Swift function affects neither bone morphogenic protein nor fibroblast growth factor signaling during early development. We conclude that Swift is a novel coactivator of Smad2 and that Swift has a critical role in embryonic TGFbeta-induced gene transcription. Our results suggest that Swift may be a general component of TGFbeta signaling.
Mol Cell Biol 2001 Jun
PMID:Swift is a novel BRCT domain coactivator of Smad2 in transforming growth factor beta signaling. 1135 98

Both human and mouse cells express an alternatively spliced variant of BRCA1, BRCA1-Delta11, which lacks exon 11 in its entirety, including putative nuclear localization signals. Consistent with this, BRCA1-Delta11 has been reported to reside in the cytoplasm, a localization that would ostensibly preclude it from playing a role in the nuclear processes in which its full-length counterpart has been implicated. Nevertheless, the finding that murine embryos bearing homozygous deletions of exon 11 survive longer than embryos that are homozygous for Brca1 null alleles suggests that exon 11-deleted isoforms may perform at least some of the functions of Brca1. We have analyzed both the full-length and the exon 11-deleted isoforms of the murine Brca1 protein. Our results demonstrate that full-length murine Brca1 is identical to human BRCA1 with respect to its cell cycle regulation, DNA damage-induced phosphorylation, nuclear localization, and association with Rad51. Surprisingly, we show that endogenous Brca1-Delta11 localizes to discrete nuclear foci indistinguishable from those found in wild-type cells, despite the fact that Brca1-Delta11 lacks previously defined nuclear localization signals. However, we further show that DNA damage-induced phosphorylation of Brca1-Delta11 is significantly reduced compared to full-length Brca1, and that gamma irradiation-induced Rad51 focus formation is impaired in cells in which only Brca1-Delta11 is expressed. Our results suggest that the increased viability of embryos bearing homozygous deletions of exon 11 may be due to expression of Brca1-Delta11 and suggest an explanation for the genomic instability that accompanies the loss of full-length Brca1.
Mol Cell Biol 2001 Jun
PMID:Impaired DNA damage response in cells expressing an exon 11-deleted murine Brca1 variant that localizes to nuclear foci. 1135 8


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