BRCA1-induced Apoptosis Involves Inactivation of ERK1/2 Activities

Abstract

Mutation in the BRCA1 gene is associated with an increased risk of breast and ovarian cancer. Recent studies have shown that the BRCA1 gene product may be important in mediating responses to DNA damage and genomic instability. Previous studies have indicated that overexpression of BRCA1 can induce apoptosis or cell cycle arrest at the G2/M border in various cell types. Although the activation of JNK kinase has been implicated in BRCA1-induced apoptosis, the role of other members of the mitogen-activated protein kinase family in mediating the cellular response to BRCA1 has not yet been examined. In this study, we monitored the activities of three members of the MAPK family (ERK1/2, JNK, p38) in MCF-7 breast cancer cells and U2OS osteosarcoma cells after their exposure to a recombinant adenovirus expressing wild type BRCA1 (Ad.BRCA1). Overexpression of BRCA1 in MCF-7 cells resulted in arrest at the G2/M border; however, BRCA1 expression in U2OS cells induced apoptosis. Although BRCA1 induced JNK activation in both cell lines, there were marked differences in ERK1/2 activation in response to BRCA1 expression in these two cell lines. BRCA1-induced apoptosis in U2OS cells was associated with no activation of ERK1/2. In contrast, BRCA1 expression in MCF-7 cells resulted in the activation of both ERK1/2 and JNK. To directly assess the role of ERK1/2 in determining the cellular response to BRCA1, we used dominant negative mutants of MEK1 as well as MEK1/2 inhibitor PD98059. Our results indicate that inhibition of ERK1/2 activation resulted in increased apoptosis after BRCA1 expression in MCF-7 cells. Furthermore, BRCA1-induced apoptosis involved activation of JNK, induction of Fas-L/Fas interaction, and activation of caspases 8 and 9. The studies presented in this report indicate that the response to BRCA1 expression is determined by the regulation of both the JNK and ERK1/2 signaling pathways in cells. Mutation in the BRCA1 gene is associated with an increased risk of breast and ovarian cancer. Recent studies have shown that the BRCA1 gene product may be important in mediating responses to DNA damage and genomic instability. Previous studies have indicated that overexpression of BRCA1 can induce apoptosis or cell cycle arrest at the G2/M border in various cell types. Although the activation of JNK kinase has been implicated in BRCA1-induced apoptosis, the role of other members of the mitogen-activated protein kinase family in mediating the cellular response to BRCA1 has not yet been examined. In this study, we monitored the activities of three members of the MAPK family (ERK1/2, JNK, p38) in MCF-7 breast cancer cells and U2OS osteosarcoma cells after their exposure to a recombinant adenovirus expressing wild type BRCA1 (Ad.BRCA1). Overexpression of BRCA1 in MCF-7 cells resulted in arrest at the G2/M border; however, BRCA1 expression in U2OS cells induced apoptosis. Although BRCA1 induced JNK activation in both cell lines, there were marked differences in ERK1/2 activation in response to BRCA1 expression in these two cell lines. BRCA1-induced apoptosis in U2OS cells was associated with no activation of ERK1/2. In contrast, BRCA1 expression in MCF-7 cells resulted in the activation of both ERK1/2 and JNK. To directly assess the role of ERK1/2 in determining the cellular response to BRCA1, we used dominant negative mutants of MEK1 as well as MEK1/2 inhibitor PD98059. Our results indicate that inhibition of ERK1/2 activation resulted in increased apoptosis after BRCA1 expression in MCF-7 cells. Furthermore, BRCA1-induced apoptosis involved activation of JNK, induction of Fas-L/Fas interaction, and activation of caspases 8 and 9. The studies presented in this report indicate that the response to BRCA1 expression is determined by the regulation of both the JNK and ERK1/2 signaling pathways in cells. Withdrawal: BRCA1-induced apoptosis involves inactivation of ERK1/2 activitiesJournal of Biological ChemistryVol. 294Issue 20PreviewThis article has been withdrawn by Ying Yan and Kenneth H. Cowan. John P. Haas, Min Kim, and Magdalene K. Sgagias could not be reached. The first author identified some issues and brought them to the attention of the Journal. Subsequently, some issues were also noted in the article by the Journal. After careful analysis of all of the original data used for preparing the figures in the publication, the following errors were identified: The Actin immunoblot in the original Fig. 1A (identified from MCF-7) was used in the immunoblot for Fig. Full-Text PDF Open Access extracellular signal regulated protein kinase phosphorylated ERK 4, 6-diamidino-2-phenylindole the cell surface receptor that also designated Apo-1 or CD95 Fas ligand c-Jun N-terminal kinase phosphorylated JNK dominant negative mitogen-activated protein kinase kinase 1 poly (ADP-ribose) polymerase TdT-mediated dUTP-biotin end labeling assay adenovirus plaque-forming units phosphate-buffered saline Breast cancer remains the most common cancer affecting women in the Western world. Although most breast cancers are sporadic, ∼10% are inheritable and associated with mutations in at least two loci,BRCA1 and BRCA2. The BRCA1 gene is located at position 17q21 of the human genome, and mutations in this gene are associated with an increased risk of development of breast and ovarian cancer (1Yang X. Lippman M.E. Breast Cancer Res. Treat. 1999; 54: 1-10Crossref PubMed Scopus (59) Google Scholar). The BRCA1 gene encodes a protein of 1864 amino acid residues that is primarily located in the nucleus (2Miki Y. Swensen J. Shattuck-Eidens D. Futreal P.A. Harshman K. Tavtigian S. Liu Q. Cochran C. Bennett L.M. Ding W. Science. 1994; 266: 66-71Crossref PubMed Scopus (5377) Google Scholar). TheBRCA1 gene product contains several domains that may effect its interaction with many other cellular proteins. The N terminus includes a domain presumably involved in the formation of homodimers and heterodimers (with the BARD1 protein) and a ring finger domain that is involved in interaction with BAP1 and E2F-1; the middle portion of BRCA1 contains a nuclear localization signal and domains that can bind to c-Myc, p53, pRB, and the DNA repair proteins RAD50 and RAD51; the C terminus includes two BRCT domains that interact with multiple factors involved in transcriptional regulation, including CtIP, p300, p53, pRB, CBP, BRCA2, RNA polymerase II, and RNA helicase A (3Wang Q. Zhang H. Fishel R. Greene M.I. Oncogene. 2000; 19: 6152-6158Crossref PubMed Scopus (73) Google Scholar, 4Deng C.X. Brodie S.G. Bioessays. 2000; 22: 728-737Crossref PubMed Scopus (280) Google Scholar). Recent studies suggest that the BRCA1 protein may be involved in regulating numerous cellular functions including DNA damage repair, gene transcription, chromosome segregation, cell cycle arrest, and apoptosis (4Deng C.X. Brodie S.G. Bioessays. 2000; 22: 728-737Crossref PubMed Scopus (280) Google Scholar). Several studies suggest a role for BRCA1 in DNA repair. First, BRCA1 interacts with RAD51, a human homologue of the yeast RecA protein involved in double-stranded DNA break repair (5Scully 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 (1332) Google Scholar, 6Chen J.J. Silver D. Cantor S. Livingston D.M. Scully R. Cancer Res. 1999; 59 (Suppl 7): 1752-1756Google Scholar). In vitro, BRCA1 can associate with the RAD50-MRE11-NBS1 complex, a functional unit implicated in homologous recombination, non-homologous end joining, and meiotic recombination. In irradiated BRCA1 is to this complex, a role in DNA repair Q. Chen S. Chen Y. Xiao J. Chen Science. 1999; PubMed Scopus Google Scholar). expression of BRCA1 cellular to and the of DNA break repair R. S. K. Chen J. Livingston D.M. Cell. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). BRCA1 interacts with proteins involved in repair, and Furthermore, the of BRCA1 with and was to be for DNA repair Y. D. P. J. 2000; PubMed Scopus Google Scholar). A by Y. D. P. J. 2000; PubMed Scopus Google for the of a that factors involved in various of DNA repair. The identified was to BRCA1 and the DNA repair factors and C Y. D. P. J. 2000; PubMed Scopus Google Scholar). results suggest that BRCA1 a that functions in multiple activities for the of genomic and the of DNA Y. D. P. J. 2000; PubMed Scopus Google Scholar). DNA repair numerous studies also suggest that BRCA1 an important role in transcriptional BRCA1 interacts with involved in transcription, RNA polymerase and RNA helicase that be a of the transcriptional S. A. 2000; PubMed Google Scholar, R. D.M. Livingston D.M. S. A. 1997; PubMed Scopus Google Scholar, T. 19: PubMed Scopus Google Scholar). BRCA1 also with several factors to as transcriptional or as c-Myc, p53, p300, CBP, CtIP, and (3Wang Q. Zhang H. Fishel R. Greene M.I. Oncogene. 2000; 19: 6152-6158Crossref PubMed Scopus (73) Google Scholar). overexpression of BRCA1 can or of (3Wang Q. Zhang H. Fishel R. Greene M.I. Oncogene. 2000; 19: 6152-6158Crossref PubMed Scopus (73) Google Scholar). The of BRCA1 in regulation of gene is not Although BRCA1 can interact with of the RNA polymerase complex, there is to its role as a of the BRCA1 protein has effect gene by the or factors S. J. Y. Q. Science. 1999; PubMed Scopus Google Scholar, Q. Zhang H. K. Greene M.I. Oncogene. PubMed Scopus Google Scholar, S. H. P. W. Q. Oncogene. 2000; 19: PubMed Scopus Google Scholar). is that the role of BRCA1 in gene is to a of and factors that are involved in cell or cell A role for BRCA1 in these is by studies that the expression of BRCA1 can a cell cycle arrest, at the G2/M K. Sgagias Y. J. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, S. Sgagias or the induction of apoptosis D. C. S. Cell. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, M.E. C. C. PubMed Scopus Google Scholar, J. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). The that the of cells or cell cycle have not yet been protein are of at least three signal pathways that cell and the of their and the of their the mitogen-activated protein can be three and The first includes the and activation by to the induction of and the of cell cycle 1997; PubMed Scopus Google Scholar). Furthermore, activation of the was to be for cell and for 1997; PubMed Scopus Google Scholar). In contrast, and are primarily by as protein and and their activation to to 1997; PubMed Scopus Google Scholar). has been to a role in apoptosis. D. C. S. Cell. 1999; Full Text Full Text PDF PubMed Scopus Google that the induction of apoptosis in U2OS cells by BRCA1 is functional JNK. J. 2000; Full Text Full Text PDF PubMed Scopus Google in MCF-7 cells and the both and of JNK results that BRCA1 expression resulted in the of JNK, Fas-L/Fas interaction, and activation and that of was for the induction of BRCA1-induced apoptosis in MCF-7 breast cancer cells J. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). that the ERK1/2 and that of may the response of cells after overexpression of were in other including the induction of apoptosis in cells after of J. M.E. Science. PubMed Scopus Google Scholar). To the by and ERK1/2 in the BRCA1-induced response in MCF-7 and U2OS we have monitored the activities of the two after BRCA1 have also the of inhibitor and a dominant negative of the MEK1 kinase the cellular response to BRCA1 in this report suggest that activation of ERK1/2 BRCA1-induced apoptosis in MCF-7 breast cancer cells and an important role for this in determining the of cells after BRCA1 The human breast cancer cell MCF-7 and the human osteosarcoma cell U2OS were from were in in an of cells were in in were in the of with involved a exposure to the cells were in The cells were with and to were the for BRCA1 was from J. S. and of The was by the BRCA1 an from the The was with DNA cells the were and in cells. for BRCA1 was by the and the A recombinant adenovirus was identified that BRCA1 of the recombinant adenovirus indicated that the was wild type and adenovirus was from J. In the MEK1 has been and two residues located in the domain and were by The MEK1 has dominant negative and can be used to the activation of ERK1/2 by wild type MEK1 Y. P. A. S. J. 1994; PubMed Scopus Google Scholar, S. H. P. Cell. 1994; Full Text PDF PubMed Scopus Google Scholar). cells were at with or an that the as no gene In two was to the cells first the with the In these were at the indicated after the The cells were with and in cell analysis for DNA was by the of the by as by the after with or cells were for were with and were the apoptosis and Biological as by the were by the and the was as Y. C. P. 1999; PubMed Scopus Google Scholar). cells were in of and was to a of The cell was in a and at for The were for and with The cells the were with for 1 at with and with in in the for 1 at The cells were with and by cells were identified by and of X. Y. Oncogene. 1997; PubMed Scopus Google Scholar). 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In contrast, no in protein were in MCF-7 cells results are with the results from and and and indicate that the overexpression of BRCA1 apoptosis in U2OS cells not in MCF-7 cells. Fas-L/Fas have been shown to an important role in mediating apoptosis J. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). To the role of Fas-L/Fas in mediating BRCA1-induced apoptosis, we monitored the of and Fas after the overexpression of BRCA1 in both U2OS and MCF-7 cells. shown in the Fig. overexpression of BRCA1 resulted in an in both and Fas expression in both cell lines. Furthermore, in both cells lines, the induction of Fas by BRCA1 was to be the effect BRCA1 expression not in apoptosis in MCF-7 cells 1 and the induction of and Fas by BRCA1 expression is not to the cell in these cells. D. C. S. 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J. 2000; PubMed Scopus Google was used to the role of ERK1/2 signaling in regulating the of BRCA1 expression the and of MCF-7 cells. the results after MCF-7 cells with for in the of of as shown in Fig. ERK1/2 was in cells in the of the inhibitor at and inhibition was at The inhibition by to a in ERK1/2 a to that by of MCF-7 cells and a to ERK1/2 1997; PubMed Scopus Google Scholar). of ERK1/2 were in MCF-7 cells not To the effect of ERK1/2 inhibition the induction of apoptosis in MCF-7 cells were with or for in the of of and with as shown in Fig. of MCF-7 cells with of not in apoptosis In contrast, of MCF-7 cells in the of in a marked in cell an in apoptosis was in MCF-7 cells with and was in cells with The of BRCA1-induced apoptosis in MCF-7 cells after with of with the inhibition of ERK1/2 be noted that of MCF-7 resulted in marked inhibition of ERK1/2 also resulted in increased BRCA1-induced apoptosis The of the effect of ERK1/2 inhibition and the induction of apoptosis after was also examined. In these MCF-7 cells were to and 1 with or various after at cells were for ERK1/2 and apoptosis. shown in Fig. of MCF-7 cells for with resulted in inhibition of ERK1/2 in both and cells. Furthermore, of MCF-7 cells with not the of ERK1/2 and no effect BRCA1-induced JNK the MCF-7 cells were for apoptosis cells with and of apoptosis was first as as after of MCF-7 cells and was at MCF-7 cells with or no of apoptosis these data suggest a inhibition of ERK1/2 and induction of apoptosis after BRCA1 overexpression in MCF-7 cells. To the induction of apoptosis in these protein from the were by Western to assess the of The of by a of apoptosis, the of cell P. D. X. Cell. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar, X. J. R. X. Cell. 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PubMed Scopus Google J. 2000; Full Text Full Text PDF PubMed Scopus Google the cell and that BRCA1-induced apoptosis involves the activation of JNK. Furthermore, expression of a dominant negative of JNK can the by BRCA1 overexpression D. C. S. Cell. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). studies by J. 2000; Full Text Full Text PDF PubMed Scopus Google that BRCA1-induced apoptosis in MCF-7 cells also involves JNK Fas-L/Fas interaction, and activation Although JNK activation may be for BRCA1-induced apoptosis, the role of other members of the mitogen-activated protein kinase including in BRCA1-induced apoptosis not been examined. ERK1/2 signaling has been shown to cell and and the induction of apoptosis by the JNK and J. M.E. Science. PubMed Scopus Google S. J. Full Text Full Text PDF PubMed Scopus Google Scholar). Furthermore, the that the response by BRCA1 overexpression in MCF-7 cells was a role for ERK1/2 in determining the cellular response to BRCA1 J. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). In this we the role of ERK1/2 and in apoptosis in U2OS and MCF-7 cells. Our results that overexpression of BRCA1 protein in U2OS osteosarcoma cells resulted in a induction of JNK and was associated with induction of apoptosis. BRCA1 overexpression in MCF-7 cells also resulted in a induction of JNK studies as well as results by J. 2000; Full Text Full Text PDF PubMed Scopus Google suggest that JNK may be for BRCA1-induced apoptosis, is not by to induce apoptosis and that other factors the of cells after BRCA1 BRCA1 expression no effect the of in both U2OS and MCF-7 signaling this is not involved in the cellular response to BRCA1 Previous studies that the induction of apoptosis by BRCA1 overexpression is associated with an in Fas-L/Fas and activation of and D. C. S. Cell. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, J. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). In this report we that overexpression of BRCA1 in both U2OS and MCF-7 cells resulted in increased Fas and Fas ligand Although the induction of Fas and Fas ligand by BRCA1 in U2OS cells resulted in activation of and and apoptosis, the in Fas-L/Fas after BRCA1 expression in MCF-7 cells not in activation of caspases and is not associated with apoptosis. the induction of Fas and the activation of JNK after BRCA1 overexpression in MCF-7 cells are not by to induce apoptosis. Although BRCA1 expression results in JNK activation in both U2OS cells and MCF-7 expression of BRCA1 ERK1/2 in these two cells lines. In U2OS BRCA1 expression was associated with a in the of BRCA1 expression in MCF-7 cells resulted in increased of ERK1/2 studies suggest that the of ERK1/2 to that of JNK can the of cells to apoptosis J. M.E. Science. PubMed Scopus Google Scholar). in this report we that inhibition of the ERK1/2 three and all resulted in apoptosis in MCF-7 cells after BRCA1 studies of the of this signal in determining cell after BRCA1 Recent studies that induction of apoptosis by the Fas-L/Fas interaction can pathways and that cell can be as type or the of the pathways of activation of and C. S. A. M.E. J. PubMed Scopus Google Scholar). MCF-7 cells C. S. A. M.E. J. PubMed Scopus Google apoptosis in these cells be activation of and and this activation after of Previous studies to these caspases that both and are for BRCA1-induced apoptosis in MCF-7 cells and that was of activation of J. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). in this report suggest that JNK activation and increased Fas expression in MCF-7 cells not in or activation and apoptosis ERK1/2 is activation of ERK1/2 after BRCA1 expression in MCF-7 cells in apoptosis. BRCA1 Fas ligand and Fas interaction in MCF-7 cells in the activation of ERK1/2 with the of the receptor Fas and the activation of the of the of and the activation of the can be by increased expression of members of the as and Y. D. S. A. PubMed Scopus Google Scholar, C. S. A. M.E. J. PubMed Scopus Google Scholar). In studies inhibition of ERK1/2 in MCF-7 cells to expression of and after a role for these in the regulation of apoptosis by ERK1/2 in MCF-7 cells. In results indicate that BRCA1 apoptosis in U2OS cells not in MCF-7 cells in Although BRCA1 expression results in JNK activation in both cell lines, the ERK1/2 activities in U2OS and MCF-7 cells after with ERK1/2 inhibition studies in MCF-7 cells indicate an important role for this in cells from BRCA1-induced apoptosis. studies be to the of BRCA1 expression the of ERK1/2 in cells and the role of signal pathways in regulating the of BRCA1 expression cell cycle inhibition and apoptosis. D. for and J. for