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• W1997799248 abstract "The BRCA1 and p53 tumor suppressors have been shown to interact and cooperate to activate transcription of p53-responsive genes. In this study, we show that BRCA1 is initially up-regulated, followed by a reduction to below basal levels in response to treatment with the DNA-damaging agents adriamycin and mitomycin C, and that the reduction of BRCA1 expression is dependent on the presence of wild-type p53. Elimination of p53 by expression of human papilloma virus E6 resulted in an inability to down-regulate BRCA1 in response to adriamycin. Ectopic expression of p53 resulted in a rapid decrease in BRCA1 protein and RNA levels and BRCA1promoter-driven luciferase activity even in null p21 cells deficient in p53-dependent G1 arrest. ATM−/− lymphoblastoid cells were deficient in their ability to reduce BRCA1 protein in response to DNA damage, whereas the wild-type counterparts reduced BRCA1 protein levels after exposure to adriamycin. These results, in conjunction with others, suggest a loop wherein BRCA1 initially participates in accumulation of p53 protein, whereas later p53 acts to reduce BRCA1 expression. The BRCA1 and p53 tumor suppressors have been shown to interact and cooperate to activate transcription of p53-responsive genes. In this study, we show that BRCA1 is initially up-regulated, followed by a reduction to below basal levels in response to treatment with the DNA-damaging agents adriamycin and mitomycin C, and that the reduction of BRCA1 expression is dependent on the presence of wild-type p53. Elimination of p53 by expression of human papilloma virus E6 resulted in an inability to down-regulate BRCA1 in response to adriamycin. Ectopic expression of p53 resulted in a rapid decrease in BRCA1 protein and RNA levels and BRCA1promoter-driven luciferase activity even in null p21 cells deficient in p53-dependent G1 arrest. ATM−/− lymphoblastoid cells were deficient in their ability to reduce BRCA1 protein in response to DNA damage, whereas the wild-type counterparts reduced BRCA1 protein levels after exposure to adriamycin. These results, in conjunction with others, suggest a loop wherein BRCA1 initially participates in accumulation of p53 protein, whereas later p53 acts to reduce BRCA1 expression. multiplicity of infection The breast and ovarian cancer susceptibility gene BRCA1has been suggested to be involved in gene transcription, DNA repair, and transcription-coupled repair (1Irminger-Finger I. Siegel B.D. Leung W.C. Biol. Chem. 1999; 380: 117-128Crossref PubMed Scopus (55) Google Scholar). Evidence for roles in these processes has come primarily from identification of interacting proteins with BRCA1. For example, binding to such proteins as Rad51 (2Scully R. Chen J. Plug A. Xiao Y. Weaver D. Feunteun J. Ashley T. Livingston D.M. Cell. 1997; 88: 265-275Abstract Full Text Full Text PDF PubMed Scopus (1316) Google Scholar) and Rad50, p95, and MRE11 (3Zhong Q. Chen C.F. Li S. Chen Y. Wang C.C. Xiao J. Chen P.L. Sharp Z.D. Lee W.H. Science. 1999; 285: 747-750Crossref PubMed Scopus (523) Google Scholar) has suggested that BRCA1 may be involved in DNA repair mechanisms, such as double strand break repair, that involve the Rad, p95, and MRE11 proteins. BRCA1 is also bound and phosphorylated by the ATM and human CDS1 DNA damage-activated kinases (3Zhong Q. Chen C.F. Li S. Chen Y. Wang C.C. Xiao J. Chen P.L. Sharp Z.D. Lee W.H. Science. 1999; 285: 747-750Crossref PubMed Scopus (523) Google Scholar, 4Cortez D. Wang Y. Qin J. Elledge S.J. Science. 1999; 286: 1162-1166Crossref PubMed Scopus (868) Google Scholar). On the other hand, BRCA1 also complexes with RNA polymerase II (6Scully R. Anderson S.F. Chao D.M. Wei W. Ye L. Young R.A. Livingston D.M. Parvin J.D. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 5605-5610Crossref PubMed Scopus (420) Google Scholar), RNA helicase A (7Anderson S.F. Schlegel B.P. Nakajima T. Wolpin E.S. Parvin J.D. Nat. Genet. 1998; 19: 254-256Crossref PubMed Scopus (338) Google Scholar), the transcriptional repressor CtIP (8, 9), and histone deacetylase components RbAP46 and RbAP48 (10Yarden R.I. Brody L.C. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 4983-4988Crossref PubMed Scopus (284) Google Scholar), and the association of BRCA1 with the polyadenylation factor CstF-50 is bridged by BARD1 (11Kleiman F.E. Manley J.L. Science. 1999; 285: 1576-1579Crossref PubMed Scopus (142) Google Scholar). These interactions suggest that BRCA1 plays some role in cellular gene transcription. It has been hypothesized that BRCA1 involvement in transcription is a means by which the protein acts in one aspect of DNA repair (12Gowen L.C. Avrutskaya A.V. Latour A.M. Koller B.H. Leadon S.A. Science. 1998; 281: 1009-1012Crossref PubMed Scopus (449) Google Scholar). The findings thatBRCA1 −/− cells are defective in transcription-coupled repair and that BRCA1 associates with such global transcription components as RNA polymerase II suggest that BRCA1 is not a specific transcriptional activator per se. However, BRCA1 has also been shown to bind individual transcription factors such as p53 and c-Myc (13Zhang H. Somasundaram K. Peng Y. Tian H. Zhang H. Bi D. Weber B.L. El-Deiry W.S. Oncogene. 1998; 16: 1713-1721Crossref PubMed Scopus (423) Google Scholar, 14Ouchi T. Monteiro A.N. August A. Aaronson S.A. Hanafusa H. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 2302-2306Crossref PubMed Scopus (333) Google Scholar, 15Wang Q. Zhang H. Kajino K. Greene M.I. Oncogene. 1998; 17: 1939-1948Crossref PubMed Scopus (190) Google Scholar). BRCA1 is able to repress c-Myc transcriptional activity, whereas it is able to enhance p53 activity similar to other transcriptional coactivators such as p300 and cAMP-responsive element-binding protein. BRCA1-specific involvement in the p53 response has been enhanced with the finding thatBRCA1 −/− embryos survive longer if one or both copies of the p53 gene are also missing (16Ludwig T. Chapman D.L. Papaioannou V.E. Efstratiadis A. Genes Dev. 1997; 11: 1226-1241Crossref PubMed Scopus (460) Google Scholar). That activation of specific genes such as p21 WAF1 andGADD45 or repression of cyclin B1 (17Somasundaram K. Zhang H. Zeng Y.X. Houvras Y. Peng Y. Zhang H. Wu G.S. Licht J.D. Weber B.L. El-Deiry W.S. Nature. 1997; 389: 187-190Crossref PubMed Scopus (471) Google Scholar, 18Harkin D.P. Bean J.M. Miklos D. Song Y.H. Truong V.B. Englert C. Christians F.C. Ellisen L.W. Maheswaran S. Oliner J.D. Haber D.A. Cell. 1999; 97: 575-586Abstract Full Text Full Text PDF PubMed Scopus (511) Google Scholar, 19MacLachlan T.K. Somasundaram K. Sgagias M. Shifman Y. Muschel R.J. Cowan K.H. El-Deiry W.S. J. Biol. Chem. 2000; 275: 2777-2785Abstract Full Text Full Text PDF PubMed Scopus (189) Google Scholar) is also mediated by BRCA1 again raises the possibility that BRCA1 effects on transcription may be specific. p53 binds to two regions of BRCA1: at the N terminus between amino acids 224 and 500 and also within the BRCT domain at the C terminus (13Zhang H. Somasundaram K. Peng Y. Tian H. Zhang H. Bi D. Weber B.L. El-Deiry W.S. Oncogene. 1998; 16: 1713-1721Crossref PubMed Scopus (423) Google Scholar, 20Chai Y.L. Cui J. Shao N. Reddy E.S.P. Rao V.N. Oncogene. 1999; 18: 63-68Crossref Scopus (157) Google Scholar). Transcriptional coactivation of p53 is dependent on the C terminus of BRCA1, as this region is required for all transcription-related events that BRCA1 performs (14Ouchi T. Monteiro A.N. August A. Aaronson S.A. Hanafusa H. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 2302-2306Crossref PubMed Scopus (333) Google Scholar). The N-terminal p53-binding region of BRCA1 has been shown to act as a dominant-negative inhibitor of p53-mediated transcription when expressed without the remainder of the BRCA1 protein, indicating that although this region is able to bind p53, the machinery needed to coactivate p53 either binds to or is present in other areas of the protein (21Somasundaram K. MacLachlan T.K. Burns T.F. Sgagias M. Cowan K.H. Weber B.L. El-Deiry W.S. Oncogene. 1999; 18: 6605-6614Crossref PubMed Scopus (56) Google Scholar). Although it is clear that one mechanism by which BRCA1 induces p53 activity is to bind directly and subsequently to coactivate transcription, another mechanism may involve increasing the stability of p53. Overexpression of BRCA1 has been shown to induce accumulation of p53 in wild-type p53-expressing cell lines (21Somasundaram K. MacLachlan T.K. Burns T.F. Sgagias M. Cowan K.H. Weber B.L. El-Deiry W.S. Oncogene. 1999; 18: 6605-6614Crossref PubMed Scopus (56) Google Scholar). This accumulation appears to depend on the presence of p14ARF, a protein that allows p53 to escape degradation induced by MDM2. BRCA1-induced p53 is then transcriptionally active and activates such downstream genes as p21 WAF1 . The effect of DNA damage on BRCA1 protein has been the subject of recent studies. Treatment of cultured cells with a variety of DNA-damaging agents, including γ-radiation, UV light, mitomycin C, and adriamycin, results in a retardation of BRCA1 protein on denaturing gels that is reversed by the addition of phosphatase, indicating phosphorylation (22Scully R. Chen J. Ochs R.L. Keegan K. Hoekstra M. Feunteun J. Livingston D.M. Cell. 1997; 90: 425-435Abstract Full Text Full Text PDF PubMed Scopus (806) Google Scholar). Interestingly, many of these studies report a reduction in BRCA1 protein and RNA levels following extended treatment with DNA-damaging agents (22Scully R. Chen J. Ochs R.L. Keegan K. Hoekstra M. Feunteun J. Livingston D.M. Cell. 1997; 90: 425-435Abstract Full Text Full Text PDF PubMed Scopus (806) Google Scholar, 23Andres, J. L., Fan, S., Turkel, G. J., Wang, J. A., Twu, N. F., Yuan, R. Q., Lamszus, K., Goldberg, I. D., and Rosen, E. M. (1998) 16, 2229–2241.Google Scholar, 24Fan S. Twu N.F. Wang J.A. Yuan R.Q. Andres J. Goldberg I.D. Rosen E.M. Int. J. Cancer. 1998; 77: 600-609Crossref PubMed Scopus (45) Google Scholar). Here we show that this effect seems to be dependent on the presence of wild-type p53 protein and that ectopic expression of p53 alone is able to down-regulate BRCA1 protein. The reduction appears to occur at the RNA level. Although BRCA1 has been proposed to act in a complementary manner to p53, we propose that this feedback loop is not unlike the one that has been described for p14ARF expression: whereas p14ARF, like BRCA1, is able to induce p53 (25Stott F.J. Bates S. James M.C. McConnell B.B. Starborg M. Brookes S. Palmero I. Ryan K. Hara E. Vousden K.H. Peters G. EMBO J. 1998; 17: 5001-5014Crossref PubMed Scopus (1007) Google Scholar), p53 is also responsible for negatively regulating p14ARF expression (26Robertson K.D. Jones P.A. Mol. Cell. Biol. 1998; 18: 6457-6473Crossref PubMed Scopus (329) Google Scholar). The culture conditions of SW480, PA1, H460, H460-Neo, H460-E6, Saos2, SkOV-3, HCT116, 03189C, and 2184D cells have been previously described (27Wu G.S. El-Deiry W.S. Clin. Can. Res. 1996; 2: 623-633PubMed Google Scholar, 28El-Deiry W.S. Tokino T. Velculescu V.E. Levy D.B. Parsons R. Trent J.M. Lin D. Mercer W.E. Kinzler K.W. Vogelstein B. Cell. 1993; 75: 817-825Abstract Full Text PDF PubMed Scopus (7900) Google Scholar, 29Wu G.S. Burns T.F. McDonald E.R. Meng R. Kao G. Muschel R. Yen T. El-Deiry W.S. Oncogene. 1999; 18: 6411-6418Crossref PubMed Scopus (101) Google Scholar). Adriamycin was obtained from the University of Pennsylvania pharmacy and added to the medium of cells at a concentration of 200 or 400 ng/ml for 18 h. Mitomycin C was obtained from Sigma and added to the medium of cells at a concentration of 20 μg/ml for 8 h. Ad-LacZ and Ad-p53 (28El-Deiry W.S. Tokino T. Velculescu V.E. Levy D.B. Parsons R. Trent J.M. Lin D. Mercer W.E. Kinzler K.W. Vogelstein B. Cell. 1993; 75: 817-825Abstract Full Text PDF PubMed Scopus (7900) Google Scholar) were obtained from B. Vogelstein (Johns Hopkins University). Viruses were propagated, titered, and amplified as described (28El-Deiry W.S. Tokino T. Velculescu V.E. Levy D.B. Parsons R. Trent J.M. Lin D. Mercer W.E. Kinzler K.W. Vogelstein B. Cell. 1993; 75: 817-825Abstract Full Text PDF PubMed Scopus (7900) Google Scholar). Western blotting was carried out essentially as described (17Somasundaram K. Zhang H. Zeng Y.X. Houvras Y. Peng Y. Zhang H. Wu G.S. Licht J.D. Weber B.L. El-Deiry W.S. Nature. 1997; 389: 187-190Crossref PubMed Scopus (471) Google Scholar) using mouse anti-human p53 monoclonal (Ab-2), mouse anti-human BRCA1 monoclonal (Ab-1), mouse anti-human p21 monoclonal (Ab-1) and mouse anti-Rb monoclonal (Ab-5) antibodies (all from Oncogene Science Inc.). Total RNA isolation and Northern blotting were carried out as described previously (28El-Deiry W.S. Tokino T. Velculescu V.E. Levy D.B. Parsons R. Trent J.M. Lin D. Mercer W.E. Kinzler K.W. Vogelstein B. Cell. 1993; 75: 817-825Abstract Full Text PDF PubMed Scopus (7900) Google Scholar). AHindIII/NotI fragment of 5.6 kilobases was excised from pCR3.1-BRCA1 (30Thakur S. Zhang H.B. Peng Y. Le H. Carroll B. Ward T. Yao J. Farid L.M. Couch F.J. Wilson R.B. Weber B.L. Mol. Cell. Biol. 1997; 17: 444-452Crossref PubMed Scopus (224) Google Scholar) and used as a probe for BRCA1Northern blots. A total of 1 × 106Saos2 cells were transfected using Superfect reagent (QIAGEN Inc., Valencia, CA) with 0.5 μg of reporter and 1.5 μg of pCEP4-p53 or vector alone. 24 h after transfection, cells were lysed and analyzed for luciferase activity as described (31Zeng Y.X. Somasundaram K. El-Deiry W.S. Nat. Genet. 1997; 15: 78-82Crossref PubMed Scopus (260) Google Scholar). Adenovirus infections of MCF7 cells were carried out at m.o.i.1 = 20 in 1% fetal bovine serum and phosphate-buffered saline. Adriamycin treatment was performed as described above. Preparation of cells for fluorescence-activated cell sorting was performed essentially as described (32van den Heuvel S. Harlow E. Science. 1993; 262: 2050-2054Crossref PubMed Scopus (970) Google Scholar). Cell sorting was performed on a Coulter Epics Elite counter. DNA content analysis was performed using MacCycle software (Phoenix Flow Systems, San Diego, CA). Floating and attached cells were trypsinized from six-well dishes and pelleted by centrifugation. Cells were resuspended in 900 μl of phosphate-buffered saline, to which 100 μl of 0.4% trypan blue dye (Sigma) was added, and incubated at room temperature for 10 min. 10 μl of this mixture was applied to a hemocytometer. Dead cells (those staining blue) were counted and compared with the total number of cells viewed in the hemocytometer. We have previously found that BRCA1 induces p53 protein accumulation (21Somasundaram K. MacLachlan T.K. Burns T.F. Sgagias M. Cowan K.H. Weber B.L. El-Deiry W.S. Oncogene. 1999; 18: 6605-6614Crossref PubMed Scopus (56) Google Scholar). Recent evidence on the factors that contribute to such a process has suggested that the effect of p53 on these factors runs contrary to what one might expect. For example, whereas MDM2 degrades p53, p53 in fact activates MDM2 transcription. On the other hand, p14ARF is able to potently stabilize p53 protein; however, p53 represses p14ARF expression. Given this evidence, we sought to determine the effect of p53 on BRCA1 expression in light of recent results suggesting that BRCA1 expression may be reduced in some cell lines exposed to DNA-damaging agents. Adriamycin is a potent DNA-damaging agent that rapidly induces a p53 response in wild-type p53-expressing cell types. We treated one wild-type (PA1), one mutant (SW480) and one null (Saos2) p53 cell line with adriamycin for 24 h and examined BRCA1 protein expression by immunoblotting. Whereas SW480 (colon carcinoma) and Saos2 (osteosarcoma) cells displayed a clear shift in mobility of BRCA1 protein as well as an apparent increase in the protein level, PA1 cells (ovarian carcinoma) appeared to have lost BRCA1 expression entirely (Fig. 1 A). We also utilized lymphoblastoid cell lines derived from ataxia telangiectasia patients. These cells lack functional activity of ATM, a kinase required for the rapid accumulation of p53 protein and phosphorylation of BRCA1 (4Cortez D. Wang Y. Qin J. Elledge S.J. Science. 1999; 286: 1162-1166Crossref PubMed Scopus (868) Google Scholar) and NBS1 (33Lim D.S. Kim S.-T. Xu B. Maser R.S. Lim J. Petrini J.H.J. Kastan M.B. Nature. 2000; 404: 613-617Crossref PubMed Scopus (672) Google Scholar). We tested the 03189C line that is null for ATM activity as well as a control line (2184D) that possesses both functional copies of ATM for their effects on BRCA1 protein expression following 24 h of adriamycin treatment. The ATM−/− cell line displayed a full shift of the BRCA1 protein, which was present in similar amounts as the BRCA1 protein in untreated cells (Fig.1 B). In the wild-type ATM-containing lymphoblastoid cell line, BRCA1 also became phosphorylated upon treatment with adriamycin; however, the protein expression level decreased significantly by 24 h post-treatment. As p53 is wild-type in these lines, it is possible that the accumulation of p53 via ATM in the normal cell line led to a reduction of BRCA1 expression. Another DNA-damaging agent (mitomycin C) was also seen to cause a repression of BRCA1 protein expression only in the PA1 and HCT116 (colon carcinoma) wild-type p53-expressing cell lines, whereas no reduction or an induction was observed in the mutant p53-expressing lines SW480 and SkOV-3 (ovarian carcinoma) (Fig. 1 C). In addition to the differences in p53 status among the seven cancer cell lines described above, they are likely different genetically in many other ways as well. To more closely draw a link between BRCA1 repression and wild-type p53 presence, we utilized the H460 lung cancer cell line that expresses wild-type p53. Two variants of this line either express the human papilloma virus E6 protein that degrades p53 (H460-E6) or carry only the backbone vector from which human papilloma virus E6 is expressed (H460-Neo). Upon treatment of these lines with either 0.2 or 0.4 μg/ml adriamycin for 24 h, only the H460-Neo line stabilized p53 protein, whereas there was no detectable p53 protein in the H460-E6 line (Fig. 2), consistent with the previously reported E6-mediated p53 degradation in this line (27Wu G.S. El-Deiry W.S. Clin. Can. Res. 1996; 2: 623-633PubMed Google Scholar). Whereas BRCA1 protein shifted in the H460-E6 line treated with adriamycin, the H460-Neo cell line displayed a marked decrease in the BRCA1 protein expression level with a similar mobility shift in the protein seen in the H460-E6 line. This reduction correlated with accumulation of p53 protein. To determine if BRCA1 repression correlated temporally with the onset of p53 protein accumulation post-treatment with adriamycin, we investigated the kinetics of BRCA1 disappearance in the H460 cell line after treatment with 0.2 μg/ml adriamycin. Total cellular RNA and protein were harvested at various time points over the course of 24 h. As early as 8 h after treatment with adriamycin, a reduction inBRCA1 RNA to below basal levels was observed (Fig.3 A). By 12 h post-treatment, BRCA1 protein had completely disappeared, whereas another tumor suppressor, pRb, remained expressed (Fig. 3 B). The reduction in BRCA1 RNA correlated with the appearance of p53 protein, and the disappearance of BRCA1 protein correlated with the appearance of the p53 transcriptional target p21WAF1. Activation of p53 expression did not affect expression of another tumor suppressor, pRb. Repression of BRCA1 did not appear to be downstream of the apoptotic effects of p53, as no signs of apoptosis in the H460 cell line were noted at 12 h, the time point after adriamycin treatment when repression of BRCA1 protein is most noticeable. We have previously determined the ID50 in response to adriamycin for this cell line to be 0.53 μg/ml (27Wu G.S. El-Deiry W.S. Clin. Can. Res. 1996; 2: 623-633PubMed Google Scholar), which is above the concentration used here and was derived from a 7–10-day treatment period. It is interesting to note that immediately upon treatment of the cells with adriamycin, BRCA1 RNA increased ∼2–3-fold, and an increase in BRCA1 protein was noted, indicating a rapid induction response of BRCA1 to DNA damage. This increase may explain why in mutant and null p53 cell lines there is apparently more BRCA1 protein present after DNA damage (Fig. 1). To potentially eliminate other pathways activated by adriamycin treatment, we ectopically expressed p53 protein using an adenovirus vector in the mutant p53-expressing cell line SW480. Infection with Ad-p53, but not with Ad-LacZ or Ad-E2F, resulted in a complete disappearance of BRCA1 protein (Fig. 4 A). Overexpression of p53 also resulted in a significant reduction inBRCA1 mRNA as well, indicating that the decrease in protein noted by accumulation of p53 by adriamycin or overexpression by p53 adenovirus may be due to lack of BRCA1 transcription (Fig. 4 B). As has been suggested in the literature, BRCA1 expression may be cell cycle-regulated, with high levels of protein in cells in S and G2/M phases and lower expression levels in cells in early G1 phase (35Ruffner H. Verma I.M. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 7138-7143Crossref PubMed Scopus (178) Google Scholar). The p21WAF1protein has been found to mediate the p53-directed G1 phase arrest (28El-Deiry W.S. Tokino T. Velculescu V.E. Levy D.B. Parsons R. Trent J.M. Lin D. Mercer W.E. Kinzler K.W. Vogelstein B. Cell. 1993; 75: 817-825Abstract Full Text PDF PubMed Scopus (7900) Google Scholar). To determine if p53 was causing the repression of BRCA1 through the action of its downstream target p21, HCT116 and DLD1 cells deleted of their respective p21-coding region were infected with p53 adenoviruses and harvested for protein and RNA. As shown in Fig. 4(C and D), p53 repressed BRCA1 protein and mRNA equally well in both p21+/+ and p21−/− cells, indicating no requirement of p21 for this repression. Interestingly, in several experiments, we found BRCA1 protein and RNA to be expressed at much lower levels in both null p21 cells used here. p21 may in fact exert positive effects on the expression level or stability of the BRCA1 transcript or protein unrelated to the cell cycle in asynchronously growing cells. To determine if p21 overexpression may be able to repress BRCA1 protein to levels seen in cases of p53 overexpression, we infected HCT116 cells with p53- and p21-expressing adenoviruses, harvested for total protein, and immunoblotted for BRCA1. Whereas some decrease in BRCA1 protein levels was noted in Ad-p21-infected cells (as expected due to a presumed G1 phase arrest), the decrease in Ad-p53-infected cells was much greater, indicating that the effect that p53 has on BRCA1 expression levels goes beyond that of halting the cell cycle and may be a direct effect on transcriptional levels. Luciferase reporter constructs with 1500, 800, or 200 bases upstream of theBRCA1 transcriptional start site (34Thakur S. Croce C.M. J. Biol. Chem. 1999; 274: 8837-8843Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar) were cotransfected into Saos2 cells with a p53 mammalian expression vector, and luciferase activity was determined. Compared with vector-alone transfections, p53 repressed all BRCA1 promoter-luciferase constructs ∼10-fold, whereas p53 expressed from the same vector was able to activate a construct containing 13 copies of the consensus p53-binding site (pG13) (Fig. 5)." @default.
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• W1997799248 title "Repression of BRCA1 through a Feedback Loop Involving p53" @default.
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• W1997799248 hasConceptScore W1997799248C186886427 @default.
• W1997799248 hasConceptScore W1997799248C33923547 @default.
• W1997799248 hasConceptScore W1997799248C38652104 @default.
• W1997799248 hasConceptScore W1997799248C41008148 @default.
• W1997799248 hasConceptScore W1997799248C54355233 @default.
• W1997799248 hasConceptScore W1997799248C86803240 @default.
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• W1997799248 hasIssue "41" @default.

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