BRCA1 physically associates with p53 and stimulates its transcriptional activity

Zhang, Hongbing; Somasundaram, Kumaravel; Peng, Yi; Tian, Hui; Zhang, Hongxiang; Bi, Daike; Weber, Barbara; El‐Deiry, Wafik S.

doi:10.1038/sj.onc.1201932

Cited by 449 publications

(392 citation statements)

References 22 publications

Supporting

Mentioning

367

Contrasting

Unclassified

Order By: Relevance

“…The failure of these promoter-BRCA1 constructs to support development indicates that overexpressed, or mis-expressed, BRCA1 blocks development. This result was anticipated, in part, because of studies which demonstrate very low levels of BRCA1 expression in normal cells, and other studies that show cellular growth-arrest or apoptosis in many cell lines which overexpress BRCA1 (Shao et al, 1996;Wilson et al, 1997;Zhang et al, 1998). When we transfected mammary cell lines with BRCA1 cDNAs linked to BRCA1 promoter sequences, we did not observe apoptosis or cellular arrest (T Lane and E Solomon, preliminary observations).…”

Section: Discussionsupporting

confidence: 50%

“…The process is complicated by cellular senescence or apoptosis in many cells engineered to overexpress the BRCA1 cDNA from heterologous promoters (Aprelikova et al, 1999;Shao et al, 1996;Wilson et al, 1997;Zhang et al, 1998). Since mouse embryos de®cient in Brca1 die early in development, a straightforward assay of function is to analyse human BRCA1 gene replacement vectors for their ability to rescue Brca1-de®cient mouse embryos.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Gene replacement with the human BRCA1 locus: tissue specific expression and rescue of embryonic lethality in mice

Lane¹,

Lin²,

Brown

et al. 2000

Oncogene

View full text Add to dashboard Cite

We have generated transgenic mice that harbor a 140 kb genomic fragment of the human BRCA1 locus (TgN´BRCA1 GEN ). We ®nd that the transgene directs appropriate expression of human BRCA1 transcripts in multiple mouse tissues, and that human BRCA1 protein is expressed and stabilized following exposure to DNA damage. Such mice are completely normal, with no overt signs of BRCA1 toxicity commonly observed when BRCA1 is expressed from heterologous promoters. Most importantly, however, the transgene rescues the otherwise lethal phenotype associated with the targeted hypomorphic allele (Brca1 DexllSA ). Brca1 7/7 ; TgN´BRCA1 GEN bigenic animals develop normally and can be maintained as a distinct line. These results show that a 140 kb fragment of chromosome 17 contains all elements necessary for the correct expression, localization, and function of the BRCA1 protein. Further, the model provides evidence that function and regulation of the human BRCA1 gene can be studied and manipulated in a genetically tractable mammalian system. Oncogene (2000) 19, 4085 ± 4090.

show abstract

Section: Discussionsupporting

confidence: 50%

Section: Introductionmentioning

confidence: 99%

Gene replacement with the human BRCA1 locus: tissue specific expression and rescue of embryonic lethality in mice

Lane¹,

Lin²,

Brown

et al. 2000

Oncogene

View full text Add to dashboard Cite

show abstract

“…BRCA1 has been shown previously to interact with a number of different proteins, including but not limited to ATF1, p53, Myc, STAT1 and the CBP-interacting protein CtIP (Ouchi et al, 1998(Ouchi et al, , 2000Wang et al, 1998;Yu et al, 1998;Zhang et al, 1998;Houvras et al, 2000). However, in a previous study describing the regulation of the cyclin-dependent kinase inhibitor p27 Kip1 by BRCA1, we determined that none of the already identified partners of BRCA1 were involved with this function (Williamson et al, 2002).…”

Section: Discussionmentioning

confidence: 83%

BRCA1 and FOXA1 proteins coregulate the expression of the cell cycle-dependent kinase inhibitor p27Kip1

et al. 2005

View full text Add to dashboard Cite

We have previously shown that the breast cancer susceptibility gene, BRCA1, can transcriptionally activate the p27 Kip1 promoter. The BRCA1-responsive element was defined as a 35 bp region from position À545 to À511. We next determined that within this region is also a potential binding site for the transcription factor Forkhead box (FOX)A1. RNA and protein analysis as well as immunohistochemistry showed that expression of FOXA1 correlated with the expression of the estrogen receptor in a panel of breast cancer cell lines and tissues. In transient transfection reporter assays, FOXA1 could activate the p27 Kip1 promoter. Cotransfection of BRCA1 and FOXA1 resulted in a synergistic activation of the p27 Kip1 promoter. Mutation of the FOXA1 DNA-binding site in the p27 Kip1 promoter-luciferase construct significantly diminished the activity of FOXA1 alone or in combination with BRCA1. Cotransfection of FOXA1 and BRCA1 resulted in a greater amount of each protein compared to transfection of each expression vector alone. The half-life of FOXA1 was increased when coexpressed with BRCA1. Electrophoretic mobility shift assay analysis demonstrated that FOXA1 could bind to a wild-type oligonucleotide containing the FOXA1 binding site in the p27 Kip1 promoter, but this binding was lost upon mutation of this FOXA1 binding site. The protein-DNA binding complex could be supershifted with an antibody directed against FOXA1. The activity of the p27 Kip1 promoter as well as FOXA1 expression was reduced in cells treated with BRCA1 siRNA, thus silencing the expression of BRCA1 protein. In summary, we identified a FOXA1 binding site within the BRCA1-responsive element of the p27 Kip1 promoter and showed that FOXA1 activated the promoter alone and in conjunction with BRCA1. Furthermore, we identified high expression of FOXA1 in breast cancer cell lines and tissues, discovered a role for BRCA1 in the regulation of p27 Kip1 transcription and a possible interaction with BRCA1.

show abstract

“…In view of our data demonstrating for the conformation mutant p53D237 ± 239 the loss of and for the DNA contact mutant p53(273H) the defectiveness in recombination inhibition, these helicase interactions could be envisioned to be of functional signi®cance in recombination control. Most interestingly, the hRad51 complex partner BRCA1 interacts with p53 between amino acids 300 ± 393 (Ouchi et al, 1998;Zhang et al, 1998). BRCA1 can be imagined to stabilize functional interactions between p53 and hRad51.…”

Section: Discussionmentioning

confidence: 99%

“…Homologous recombination appears to be essential during the normal development of mammalian organisms, as can be deducted from the embryonic lethal phenotype of both rad51 nullizygotes (Lim and Hasty, 1996;Tsuzuki et al, 1996), and of BRCA17/7 mice, lacking the tumor suppressor BRCA1 (Hakem et al, 1997;Ludwig et al, 1997), a complex partner of Rad51 (Scully et al, 1997). Survival of the embryos in both knockouts can be prolonged by concomitant knockout of p53, indicating genetic interactions between p53 and Rad51, as well as between p53 and BRCA1 in addition to physical interactions described before (StuÈ rzbecher et al, 1996;Ouchi et al, 1998;Zhang et al, 1998). Previous work has demonstrated that p53 inhibits homologous DNA exchanges in mitotically growing cells (WiesmuÈ ller et al, 1996;Bertrand et al, 1997;Mekeel et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

Dissociation of the recombination control and the sequence-specific transactivation function of P53

et al. 1999

View full text Add to dashboard Cite

Recently, we described a new biological function of p53 in inhibiting recombination processes when encountering mismatches in heteroduplexes (DudenhoÈ er et al., 1998). Here, we characterized protein domains of p53 participating in this process by in vitro analysis of mutated p53 proteins, and by applying our SV40-based assay system on monkey cells, which express di erent p53 variants. We present evidence that both binding of arti®cial recombination intermediates and p53-dependent recombination control require an intact p53 core and the oligomerization domain, strongly suggesting that the recognition of DNA undergoing recombination represents an essential step of this genomic surveillance mechanism. Further analyses indicated a role of the C-terminus in negatively regulating recombination control, an e ect which can be neutralized by concurrent mismatch recognition. p53 lacking the oligomerization domain totally lost its ability to suppress homologous recombination. The cancer-related mutant p53(273H) was also signi®cantly defective in this function, although we observed only twofold reductions in the corresponding transactivation activities on p53-response elements in episomal constructs. HDM2, an inhibitor of p53's transcriptional and growth regulatory activities, interfered with the inhibition of DNA exchange processes by p53 only weakly. Thus, functions of p53 in recombination control can be structurally dissociated from p53-dependent transcriptional transactivation.

show abstract

BRCA1 physically associates with p53 and stimulates its transcriptional activity

Cited by 449 publications

References 22 publications

Gene replacement with the human BRCA1 locus: tissue specific expression and rescue of embryonic lethality in mice

Gene replacement with the human BRCA1 locus: tissue specific expression and rescue of embryonic lethality in mice

BRCA1 and FOXA1 proteins coregulate the expression of the cell cycle-dependent kinase inhibitor p27Kip1

Dissociation of the recombination control and the sequence-specific transactivation function of P53

Contact Info

Product

Resources

About