Identification of a novel transcriptional repressor element located in the first intron of the human BRCA1 gene

Suen, Ting-Chung; Goss, Paul E.

doi:10.1038/sj.onc.1204078

Cited by 20 publications

(34 citation statements)

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“…These include monoallelic or biallelic deletion of the BRCA1 locus and transcriptional silencing by promoter methylation (56). The latter effect may also be achieved either by loss of proteins positively regulating BRCA1 expression (58) or by an increase in proteins playing a role of its negative regu- lators (59,60). In the model shown in Fig.…”

Section: Discussionmentioning

confidence: 99%

Structural Determinants of BRCA1 Translational Regulation

Sobczak

Krzyżosiak

2002

Journal of Biological Chemistry

108

103

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The BRCA1 gene is involved in sporadic breast and ovarian cancer mainly through reduced expression. BRCA1 mRNAs containing different leader sequences show different patterns of expression. In a normal mammary gland mRNA with a shorter leader sequence, 5-UTRa is expressed only, whereas in breast cancer tissue mRNA with a longer leader, 5-UTRb is expressed also. We show that the translation efficiency of transcripts containing 5-UTRb is 10 times lower than those containing 5-UTRa. The structures of 5-UTRa and 5-UTRb were determined by chemical and enzymatic probing aided by a new method developed for monitoring the number of co-existing stable conformers. Specific factors responsible for reduced translation of mRNA containing 5-UTRb were determined using a variety of transcripts with mutations in the leader sequence. These factors include a stable secondary structure formed by truncated Alu element and upstream AUG codons. The novel mechanism by which BRCA1 may be involved in sporadic breast and ovarian cancer is proposed. It is based on the expression patterns of BRCA1 mRNAs and differences in their translatability. According to this mechanism the deregulation of the BRCA1 transcription in cancer, resulting in a higher proportion of translationally inhibited transcripts containing 5-UTRb, contributes to the decrease in the BRCA1 protein observed in sporadic breast and ovarian cancers.Breast cancer is one of the leading causes of death among women, and the lifetime risk of developing this malignancy has reached 10% in many countries in the Western world. The great majority of breast cancer is sporadic, and only a small proportion has been attributed to germ line mutations in predisposing genes (1). BRCA1 was the first major breast/ovarian cancer susceptibility gene identified (2). Its germ line mutations contribute to about 3% of all breast cancers in Caucasians. On the other hand, somatic mutations in this tumor suppressor gene are very rare in sporadic breast cancer (3) and ovarian cancer (4).Several lines of evidence strongly suggest the involvement of BRCA1 in the etiology of sporadic breast and ovarian cancer through reduced expression. Decreased levels of BRCA1 mRNA are frequently observed in breast tumors (5-8) and ovarian tumors (9). Lower or undetectable levels of expression of the BRCA1 protein have been observed in sporadic breast cancer (10). The majority of high grade ductal carcinomas express very low levels of the BRCA1 protein in comparison to normal mammary tissue and lobular cancers (11). The reduction of the BRCA1 protein has also been observed in sporadic ovarian carcinomas (9, 11). Antisense inhibition of BRCA1 expression enhances the growth rate of the breast cancer cell line (5), and conversely, the overexpression of BRCA1 in breast and ovarian cancer cell lines results in growth inhibition (12).Different mechanisms have been shown to be responsible for the reduced expression of BRCA1. One of them is allelic deletion at the BRCA1 locus (LOH) 1 observed in about 40 -80% of sporadic breast c...

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Section: Discussionmentioning

confidence: 99%

Structural Determinants of BRCA1 Translational Regulation

Sobczak

Krzyżosiak

2002

Journal of Biological Chemistry

108

103

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“…Id proteins contain helix-loop-helix (HLH) dimerization motifs, but do not have the DNA-binding basic domain found present in basic HLH proteins, thereby allowing them to function as inhibitors of bHLH transcription factors. A CREB/ATF-1 site within the BRCA1 proximal promoter (Atlas et al, 2001) and a transcriptional repressor element in the first intron of BRCA1 (Suen and Goss, 2001) function, respectively, as constitutive positive and negative regulatory elements for BRCA1. Several studies indicate that activation of the p53 tumor suppressor protein inhibits BRCA1 gene expression (Arizti et al, 2000;MacLachlan et al, 2000), raising the possibility of a p53:BRCA1 negative feedback loop, since BRCA1 binds p53 and co-activates it transcriptional activity (see below, ''Regulation of Transcription'').…”

Section: Regulation Of Brca1 Expressionmentioning

confidence: 99%

BRCA1 gene in breast cancer

Rosen

Fan

Pestell

et al. 2003

Journal Cellular Physiology

242

195

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The BRCA1 gene was identified and cloned in 1994 based on its linkage to early onset breast cancer and breast-ovarian cancer syndromes in women. While inherited mutations of BRCA1 are responsible for about 40-45% of hereditary breast cancers, these mutations account for only 2-3% of all breast cancers, since the BRCA1 gene is rarely mutated in sporadic breast cancers. However, BRCA1 expression is frequently reduced or absent in sporadic cancers, suggesting a much wider role in mammary carcinogenesis. Since BRCA1 was cloned in 1994, its molecular function has been the subject of intense investigation. These studies have revealed multiple functions of the BRCA1 that may contribute to its tumor suppressor activity, including roles in: cell cycle progression, several highly specialized DNA repair processes, DNA damage-responsive cell cycle checkpoints, regulation of a set of specific transcriptional pathways, and apoptosis. Many of these functions are linked to protein:protein interactions involving different portions of the 1,863 amino acid (aa) BRCA1 protein. BRCA1 functions in cell cycle progression and the DNA damage response appear to be regulated by distinct and specific phosphorylation events, but the molecular pathways activated by these phosphorylations are only beginning to be unraveled. In addition, the reason that BRCA1 mutation carriers develop specific tumor types (breast and ovarian cancers in women and possibly prostate cancers in men) is not clearly understood. Elucidation of the precise molecular functions of the BRCA1 gene product will greatly enhance our understanding of the pathogenesis of hereditary as well as sporadic mammary carcinogenesis.

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“…17 Many of these elements have been demonstrated to regulate basal BRCA1 transcriptional activity, 18 several distal regions have also been identified which exert either negative or positive regulation on the BRCA1 promoter, although the factors which bind these sites have yet to be determined. 19,20 Wang et al initially described regulation of both human and murine forms of BRCA1 by the two prototypical members of the Rb-E2F pathway, Rb and E2F1, in a transgenic mouse model. 21 The E2F family of transcription factors can be sub-divided into activating (E2F1-3a) and repressive (E2F3b-5; 6-8) proteins, the transcriptional activities of these factors are dependent on their interactions with members of the Dp family (Dp1 and Dp2) and the repressive pocket proteins, (Rb, p130 and p107).…”

Section: Introductionmentioning

confidence: 99%

Basal repression of BRCA1 by multiple E2Fs and pocket proteins at adjacent E2F sites

Bindra¹,

Glazer²

2006

Cancer Biology & Therapy

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The BRCA1 gene is rarely mutated in sporadic tumors, although numerous studies suggest that the expression of this critical tumor suppressor gene is frequently downregulated in tumors derived from a wide range of tissues. However, little is known regarding the mechanisms by which BRCA1 is transcriptionally regulated in human cells in vivo. We have shown recently that the tumor microenvironmental stress of hypoxia induces an E2F-dependent repression of BRCA1 in cancer cells. Here, we report that multiple E2Fs and associated factors bind the BRCA1 promoter at two adjacent E2F sites in the proximal promoter region of the gene, as detected by quantitative chromatin immunoprecipitation (ChIP) analysis. Intriguingly, our data suggest that E2F1 and E2F4 bind the BRCA1 proximal promoter simultaneously at the two E2F sites, although E2F4 appears to be the predominant E2F bound in log-phase cells. In contrast to previous studies, we have also detected promoter occupancy by the pocket proteins p130 and p107, but not Rb, our data indicate that E2F4 and p130/p107 complexes basally repress the BRCA1 promoter. We find that binding by these factors requires both intact E2F sites, which suggests a novel interaction between adjacent promoter elements. Taken together, these findings provide an enhanced molecular portrait of BRCA1 transcriptional regulation by E2Fs and pocket proteins, they enhance our understanding of regulation by repressive E2F complexes at target genes in vivo. Furthermore, the identification of E2F4 and p130/ p107 complexes as basal repressors of BRCA1 expression may facilitate the development of strategies based on disruption of these interactions to rescue BRCA1 expression in human tumors.

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Identification of a novel transcriptional repressor element located in the first intron of the human BRCA1 gene

Cited by 20 publications

References 57 publications

Structural Determinants of BRCA1 Translational Regulation

Structural Determinants of BRCA1 Translational Regulation

BRCA1 gene in breast cancer

Basal repression of BRCA1 by multiple E2Fs and pocket proteins at adjacent E2F sites

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