BRCA1 Affects Lipid Synthesis through Its Interaction with Acetyl-CoA Carboxylase

Germ line alterations in BRCA1 (breast cancer susceptibility gene 1) are associated with an increased susceptibility to breast and ovarian cancer. BRCA1 acts as a scaffold protein implicated in multiple cellular functions, such as transcription, DNA repair, and ubiquitination. However, the molecular mechanisms responsible for tumorigenesis are not yet fully understood. We have recently demonstrated that BRCA1 interacts in vivo with acetyl coenzyme A carboxylase α (ACCA) through its tandem of BRCA1 C terminus (BRCT) domains. To understand the biological function of the BRCA1·ACCA complex, we sought to determine whether BRCA1 is a regulator of lipogenesis through its interaction with ACCA. We showed here that RNA inhibition-mediated down-regulation of BRCA1 expression induced a marked increase in the fatty acid synthesis. We then delineated the biochemical characteristics of the complex and found that BRCA1 interacts solely with the phosphorylated and inactive form of ACCA (P-ACCA). Finally, we demonstrated that BRCA1 affects lipid synthesis by preventing P-ACCA dephosphorylation. These results suggest that BRCA1 affects lipogenesis through binding to P-ACCA, providing a new mechanism by which BRCA1 may exert a tumor suppressor function. Germ line alterations in BRCA1 (breast cancer susceptibility gene 1) are associated with an increased susceptibility to breast and ovarian cancer. BRCA1 acts as a scaffold protein implicated in multiple cellular functions, such as transcription, DNA repair, and ubiquitination. However, the molecular mechanisms responsible for tumorigenesis are not yet fully understood. We have recently demonstrated that BRCA1 interacts in vivo with acetyl coenzyme A carboxylase α (ACCA) through its tandem of BRCA1 C terminus (BRCT) domains. To understand the biological function of the BRCA1·ACCA complex, we sought to determine whether BRCA1 is a regulator of lipogenesis through its interaction with ACCA. We showed here that RNA inhibition-mediated down-regulation of BRCA1 expression induced a marked increase in the fatty acid synthesis. We then delineated the biochemical characteristics of the complex and found that BRCA1 interacts solely with the phosphorylated and inactive form of ACCA (P-ACCA). Finally, we demonstrated that BRCA1 affects lipid synthesis by preventing P-ACCA dephosphorylation. These results suggest that BRCA1 affects lipogenesis through binding to P-ACCA, providing a new mechanism by which BRCA1 may exert a tumor suppressor function. BRCA1 (breast cancer susceptibility gene 1) was the first susceptibility gene linked to breast and ovarian cancer (1Miki Y. Swensen J. Shattuck-Eidens D. Futreal P.A. Harshman K. Tavtigian S. Liu Q. Cochran C. Bennett L.M. Ding W. Bell R. Rosenthal J. Hussey C. Tran T. McClure M. Frye C. Haltier T. Phelps R. Haugen-Strano A. Katcher H. Yakumo K. Gholami Z. Shaffer D. Stone S. Bayer S. Wray C. Bogden R. Dayananth P. Ward J. Tonin P. Narod S. Bristow P.K. Norris F.H. Helvering L. Morrison P. Rosteck P. Lai M. Barrett J.C. Lewis C. Neuhausen S. Cannon-Albright L. Goldgar D. Wiseman R. Kamb A. Skolnick M.H. Science. 1994; 266: 66-71Crossref PubMed Scopus (5303) Google Scholar). Germ line mutations of BRCA1 are found in about 50% of patients with inherited breast cancer and up to 90% of families with breast and ovarian cancer susceptibility (1Miki Y. Swensen J. Shattuck-Eidens D. Futreal P.A. Harshman K. Tavtigian S. Liu Q. Cochran C. Bennett L.M. Ding W. Bell R. Rosenthal J. Hussey C. Tran T. McClure M. Frye C. Haltier T. Phelps R. Haugen-Strano A. Katcher H. Yakumo K. Gholami Z. Shaffer D. Stone S. Bayer S. Wray C. Bogden R. Dayananth P. Ward J. Tonin P. Narod S. Bristow P.K. Norris F.H. Helvering L. Morrison P. Rosteck P. Lai M. Barrett J.C. Lewis C. Neuhausen S. Cannon-Albright L. Goldgar D. Wiseman R. Kamb A. Skolnick M.H. Science. 1994; 266: 66-71Crossref PubMed Scopus (5303) Google Scholar, 2Couch F.J. Weber B.L. Hum. Mutat. 1996; 8: 8-18Crossref PubMed Scopus (270) Google Scholar). Frequent loss of the wild-type allele in tumors of BRCA1 mutation carriers suggests that BRCA1 acts as a tumor suppressor gene. However, although BRCA1 has been implicated in a number of cellular processes including the DNA damage repair (3Starita L.M. Parvin J.D. Curr. Opin. Cell Biol. 2003; 15: 345-350Crossref PubMed Scopus (191) Google Scholar), the biological role of BRCA1 remains unclear. The BRCA1 gene encodes an 1863-amino acid protein with a tandem of two BRCA1 C terminus (BRCT) 5The abbreviations used are: BRCT, BRCA1 C terminus; ACCA, acetyl coenzyme A carboxylase α; FAS, fatty acid synthase; AMPK, AMP-activated protein kinase; SCD-1, stearoyl-coA desaturase-1; SREBP-1, sterol regulatory element-binding protein-1; LXR, liver X receptor; AICAR, 5-aminoimidazole-4-carboxamide riboside; λPPase, λ protein phosphatase; RT, reverse transcription; GST, glutathione S-transferase; siRNA, small interfering RNA; RNAi, RNA inhibition; P-ACCA, phosphorylated and inactive form of ACCA. domains at its C-terminal region (4Koonin E.V. Altschul S.F. Bork P. Nat. Genet. 1996; 13: 266-268Crossref PubMed Scopus (360) Google Scholar, 5Bork P. Hofmann K. Bucher P. Neuwald A.F. Altschul S.F. Koonin E.V. FASEB J. 1997; 11: 68-76Crossref PubMed Scopus (661) Google Scholar, 6Callebaut I. Mornon J.P. FEBS Lett. 1997; 400: 25-30Crossref PubMed Scopus (485) Google Scholar). The majority of disease-associated BRCA1 mutations results in a truncated product with loss of one or two BRCT domains (2Couch F.J. Weber B.L. Hum. Mutat. 1996; 8: 8-18Crossref PubMed Scopus (270) Google Scholar). BRCT domains function as protein-protein interaction modules (7Huyton T. Bates P.A. Zhang X. Sternberg M.J. Freemont P.S. Mutat. Res. 2000; 460: 319-332Crossref PubMed Scopus (132) Google Scholar). Recently, it has been shown that a subset of tandem of BRCT domains, including those of BRCA1, function as phosphopeptide-binding modules (8Manke I.A. Lowery D.M. Nguyen A. Yaffe M.B. Science. 2003; 302: 636-639Crossref PubMed Scopus (551) Google Scholar, 9Rodriguez M. Yu X. Chen J. Songyang Z. J. Biol. Chem. 2003; 278: 52914-52918Abstract Full Text Full Text PDF PubMed Scopus (192) Google Scholar, 10Yu X. Chini C.C. He M. Mer G. Chen J. Science. 2003; 302: 639-642Crossref PubMed Scopus (690) Google Scholar). We previously identified acetyl-CoA carboxylase α (ACCA) as a novel partner of BRCA1 (11Magnard C. Bachelier R. Vincent A. Jaquinod M. Kieffer S. Lenoir G.M. Venezia N.D. Oncogene. 2002; 21: 6729-6739Crossref PubMed Scopus (81) Google Scholar). Notably, the binding of ACCA is mediated by the tandem of BRCT domains of BRCA1, and it is abolished by tumor-associated mutations that affect these domains. Thus, the in vivo interaction of ACCA and BRCA1 is likely to be important for BRCA1-mediated tumor suppression. ACCA is the rate-limiting enzyme for long chain fatty acid synthesis that catalyzes the carboxylation of acetyl-CoA to malonyl-CoA (12Kim K.S. Lee J.K. Kim K.H. Biochem. Soc. Trans. 1997; 25: 1211-1215Crossref PubMed Scopus (8) Google Scholar). Malonyl-CoA is then used for long chain fatty acid synthesis by fatty acid synthase (FAS). A number of critical ACCA phosphorylation sites have been identified (13Davies S.P. Sim A.T. Hardie D.G. Eur. J. Biochem. 1990; 187: 183-190Crossref PubMed Scopus (219) Google Scholar). More specifically, phosphorylation on Ser79 by the AMP-activated protein kinase (AMPK) is responsible for the inactivation of ACCA (14Winder W.W. Wilson H.A. Hardie D.G. Rasmussen B.B. Hutber C.A. Call G.B. Clayton R.D. Conley L.M. Yoon S. Zhou B. J. Appl. Physiol. 1997; 82: 219-225Crossref PubMed Scopus (61) Google Scholar). To explore new functions of BRCA1 that may contribute to its tumor suppressor activity, we investigated functional features of the BRCA1·ACCA complex (11Magnard C. Bachelier R. Vincent A. Jaquinod M. Kieffer S. Lenoir G.M. Venezia N.D. Oncogene. 2002; 21: 6729-6739Crossref PubMed Scopus (81) Google Scholar). We first examined the biological properties of BRCA1 with respect to those of ACCA and found that BRCA1 silencing increases cellular lipid synthesis. We then explored the biochemical characteristics of the complex BRCA1·ACCA: BRCA1 interacts solely with the phosphorylated and inactive form of ACCA (P-ACCA), and the formation of the BRCA1·P-ACCA complex interferes with ACCA activity by preventing P-ACCA dephosphorylation. Therefore, we identified a new function of BRCA1 that is to modulate lipid synthesis through its phospho-dependent binding to ACCA. Chemicals—The primary antibodies used were as follows: monoclonal antibody to human BRCA1 (OP92) (Oncogene Research Products), monoclonal antibody to actin (ICN Biochemicals), polyclonal antibody to ACCA (ACCAL3) as previously described (11Magnard C. Bachelier R. Vincent A. Jaquinod M. Kieffer S. Lenoir G.M. Venezia N.D. Oncogene. 2002; 21: 6729-6739Crossref PubMed Scopus (81) Google Scholar), and polyclonal antibody to P-ACCA (P-ACCA (S79)) (Upstate Biotechnology). The specificity of the P-ACCA(S79) antibody was tested by pretreatment of the antibody with the phosphopeptide immunogen and by pretreating the blot with phosphatase (Upstate Biotechnology). Secondary antibodies were peroxidase-conjugated anti-mouse or anti-rabbit immunoglobulins (Amersham Biosciences). 5-Aminoimidazole-4-carboxamide riboside (AICAR) was purchased from Toronto Research Chemicals. λ protein phosphatase (λPPase) was purchased from Biolabs. Expression Vectors—The pCDNA3β plasmid expressing human BRCA1 protein was previously described (15Scully 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 (808) Google Scholar). The ACCA sequence corresponding to N-terminal (4019 bp) fragment (ACCA-N) was PCR-amplified from human cDNA library, using respectively the primers Nter-F 5′-GCCTCGAGGAATAATGGATGAACCATC-3′ and Nter-R 5′-AAGCGGCCGCTGTGCAACCAGGAAAGTAAG-3′. The cDNA fragment was subcloned into the XhoI/NotI sites of pCDNA3.1/Myc-His (Invitrogen) and sequenced. The ACCA-N-S79A mutant was generated by site-directed mutagenesis (QuikChange XL site-directed mutagenesis kit; Stratagene) with the following primers: 5′-CATAAGGTCCAGCATGGCTGGCTTGCACCTAG-3′ and 5′-CTAGGTGCAAGCCAGCCATGCTGGACCTTATG-3′ and sequenced. Cell Culture and Plasmid Transfections—MCF7 human breast cancer cells were maintained in Dulbecco's modified Eagle's medium containing 1 g/liter of glucose supplemented with 10% fetal calf serum, 100 μg/ml streptomycin, and 100 units/ml of penicillin. When indicated, 0.5 mm of AICAR was added to cell medium. Bosc human embryonic kidney cells were maintained in Dulbecco's modified Eagle's medium containing 4.5 g/liter of glucose supplemented as above. MCF10A normal mammary epithelial cells were maintained in Dulbecco's modified Eagle's medium/Ham's F-12 medium supplemented as described (16Debnath J. Muthuswamy S.K. Brugge J.S. Methods. 2003; 30: 256-268Crossref PubMed Scopus (1551) Google Scholar). For transfection, MCF7 cells were plated at 4 × 105 cells/plate in a 6-well flask 24 h before transfection. The cells were transfected with 2 μg of plasmid and 10 μl of ExGen 500 (Euromedex) following the supplier procedure. h transfection, the cells were for or Bosc cells were transfected with 4 μg of plasmid and μl of ExGen 500 (Euromedex) following the supplier procedure. h transfection, the cells were The were and then in the number of that were for and cells were in mm mm 2 mm 10% supplemented with and phosphatase mm mm and 1 mm and were as described (11Magnard C. Bachelier R. Vincent A. Jaquinod M. Kieffer S. Lenoir G.M. Venezia N.D. Oncogene. 2002; 21: 6729-6739Crossref PubMed Scopus (81) Google Scholar). indicated, the of the corresponding to the were using cells were in supplemented with and phosphatase as the cells were in and as the cells were for 1 h with 0.5 mm of AICAR by in and the cells were with before was as described (11Magnard C. Bachelier R. Vincent A. Jaquinod M. Kieffer S. Lenoir G.M. Venezia N.D. Oncogene. 2002; 21: 6729-6739Crossref PubMed Scopus (81) Google Scholar). The of was examined by indicated, the protein were with of for 1 h at before by was on cell previously with of cells were plated at × 105 cells/plate in a 6-well flask 24 h before with small interfering RNA The were as and The were as follows: and The DNA were to a The cells were transfected with of and μl of (Invitrogen) using the of the The cells were for or h transfection. RNA was using the the and of RNA were examined by RNA was by on a containing μg/ml in with of of RNA The was by of μg of RNA and of a of used were to the cDNA fragment from to of the BRCA1 gene and S. D. Lenoir G. L. R. J. 1997; PubMed Scopus Google Scholar). The were using the The used was as described by the The were on a containing μg/ml and the of the corresponding to the wild-type BRCA1 and to the were using A using the primers was on RNA to the of DNA in the RNA S. D. Lenoir G. L. R. J. 1997; PubMed Scopus Google Scholar). RNA was as above. The was as described Y. J. H. J. Res. Full Text Full Text PDF PubMed Scopus Google Scholar). were first from 1 μg of RNA in the of 100 of (Invitrogen) using and primers was in a of μl containing μl of a of the μl of from the DNA and of the and reverse primers The of the primers and for are For a was generated with of cDNA in the plasmid was in and of the was by of the of the and by the and with the The were using The results are as by 2 (Amersham was added to the medium. 4 h of at the cells were with and and the were to J. M. J. Biol. Chem. Full Text PDF PubMed Google Scholar). was by The were for protein into was of by Therefore, lipid and lipid were on For of the were in acid The lipid and were by in The lipid were into 50% and was by The were for protein are as the was with a For the of lipid the of the results was using the The for was at BRCA1 the role of BRCA1 in fatty acid we used a on MCF7 of BRCA1 expression with the was by a using a BRCA1 RNA as a S. D. Lenoir G. L. R. J. 1997; PubMed Scopus Google and by the expression of BRCA1 by and BRCA1 protein by with MCF7 cells transfected with the with on the of ACCA protein A and To of BRCA1 silencing on lipid MCF7 cells transfected with or were to of into cellular of MCF7 cells transfected with was increased to of the in the cells transfected with To the of BRCA1 silencing on the lipid the lipid were by The majority of in cells was into as previously described K. W. G. Res. 2003; Google Scholar, W. C.A. A. Res. 2003; Google Scholar). BRCA1 down-regulation into to increase by fatty acid synthesis was increased with a and synthesis was increased by with a increase was found the of synthesis is that of synthesis in with that ACCA the synthesis of not K. G. Res. PubMed Scopus Google Scholar). lipid are in with the increase into cellular the that BRCA1 increased lipogenesis through fatty acid synthesis of synthesis the that BRCA1 acts through of To that the increase in lipogenesis was not to of lipid synthesis we examined gene expression of in We first expression of a regulator of lipogenesis D. B. P. P. PubMed Scopus Google Scholar). of and using showed a small in cells transfected with was not and and was not with the increase of lipogenesis in it likely not for increase in lipogenesis We then the expression of ACCA and FAS, by SREBP-1, and the enzyme SCD-1, the of ACCA, FAS, and were not modified by BRCA1 silencing Finally, SREBP-1, and are by we expression of and J. Res. Full Text Full Text PDF PubMed Scopus Google Scholar). was found of and We examined the expression of ACCA and blot using and antibodies showed that the expression of was not by BRCA1 silencing these that the increase in lipogenesis was of To the role of BRCA1 in MCF7 cells were transfected with expression plasmid BRCA1 and were to these expression of BRCA1 protein was increased to the of ACCA protein A and these cells that BRCA1, of into cellular was to of the in cells Therefore, of BRCA1 to the as BRCA1 silencing increased the role of BRCA1 in We the of gene silencing of BRCA1 on breast epithelial cells to MCF7 of BRCA1 the expression of BRCA1 and BRCA1 protein the expression of ACCA A and of into cellular was increased in with the cells these results that down-regulation of BRCA1 an increase in cellular lipid synthesis of a and that BRCA1 fatty acid synthesis. BRCA1 with that BRCA1 interacts with ACCA (11Magnard C. Bachelier R. Vincent A. Jaquinod M. Kieffer S. Lenoir G.M. Venezia N.D. Oncogene. 2002; 21: 6729-6739Crossref PubMed Scopus (81) Google to BRCA1 affects fatty acid synthesis through has been shown that phosphorylation and of ACCA its inactivation and and as the mechanism of the More specifically, inactivation of ACCA is by phosphorylation on (14Winder W.W. Wilson H.A. Hardie D.G. Rasmussen B.B. Hutber C.A. Call G.B. Clayton R.D. Conley L.M. Yoon S. Zhou B. J. Appl. Physiol. 1997; 82: 219-225Crossref PubMed Scopus (61) Google Therefore, to BRCA1 fatty acid we tested whether BRCA1 with phosphorylated and inactive form of ACCA, For we used the P-ACCA(S79) antibody purchased from To first the specificity of antibody we it in and on Bosc cell with that from and in showed that antibody not the form of ACCA, antibody a was on Bosc cells transfected with expression plasmid the N-terminal of ACCA (ACCA-N) or its form on Ser79 to P-ACCA(S79) antibody not the N-terminal of ACCA it the wild-type antibody and ACCA-N-S79A For the specificity of the antibody was using Bosc cells transfected as above. P-ACCA(S79) antibody the Therefore, the specificity of the P-ACCA(S79) antibody for phosphorylated form of ACCA on Ser79 was demonstrated to its in the following To whether BRCA1 with P-ACCA, two were using a protein were on MCF7 using the P-ACCA(S79) antibody showed that the BRCA1 BRCT domains P-ACCA to determine whether BRCA1 interacts with P-ACCA in from Bosc cells transfected with expression plasmid BRCA1 were with P-ACCA(S79) antibody and by shown in were with the and an in the of 2 and in to the marked with P-ACCA(S79) antibody We that the of used in was by using anti-rabbit antibody and Therefore, BRCA1 associated with P-ACCA in the we not P-ACCA in with BRCA1, was to a of the The of these that ACCA phosphorylated at Ser79 interacts with the BRCT domains in as as with BRCA1 in BRCA1 and determine whether BRCA1 P-ACCA and ACCA or P-ACCA, were on MCF7 that first been with to blot using P-ACCA(S79) antibody P-ACCA in the of ACCA blot of the using antibody that phosphorylated and of ACCA showed that abolished the interaction BRCA1 BRCT domains and ACCA on the of ACCA, these results that the BRCA1·ACCA interaction on the phosphorylation of ACCA. We investigated whether the of BRCA1·ACCA was on the of cellular has been shown that that cellular AMPK, to phosphorylation and inactivation of ACCA. are by of cells with AICAR, which of or Hardie D.G. Eur. Biochem. PubMed Scopus Google Scholar). Therefore, were to MCF7 in 0.5 mm AICAR for 1 or to or of ACCA, these cell showed of P-ACCA in the of ACCA and the of with the of P-ACCA in the cell Therefore, that the interaction BRCA1 and ACCA is and that BRCA1 P-ACCA in a of ACCA by we that BRCA1 a phosphorylated and inactive form of ACCA, we whether BRCA1 modulate ACCA To we examined whether binding to BRCA1 ACCA from and its were on of MCF7 cells previously with to a and the were with by showed that the of ACCA to the BRCT domains ACCA was phosphorylated as shown by that an ACCA region the Ser79 was from in the BRCA1·ACCA To whether BRCA1 ACCA from we examined the of BRCA1 silencing on the of P-ACCA dephosphorylation. MCF7 cells with AICAR for 1 of P-ACCA was AICAR was at the of the of P-ACCA AICAR and was 1 h as shown by We that AICAR on the of ACCA by using To whether the of BRCA1 ACCA AICAR was on MCF7 cells previously transfected with these the of P-ACCA in MCF7 cells transfected with was to that of MCF7 cells as previously shown in in cells transfected with of ACCA and was as as 10 AICAR C and these cells transfected with AICAR on the of ACCA as shown by using BRCA1 silencing was not by AICAR and the of These results that first BRCA1 P-ACCA from and BRCA1 silencing results in an of ACCA. Therefore, the of the BRCA1·P-ACCA complex formation P-ACCA to be BRCA1 through with demonstrated that in cells with AICAR, BRCA1 P-ACCA to be we whether BRCA1 silencing induced an increase in fatty acid synthesis through its to To MCF7 cells transfected with were with AICAR for 1 h before and for the of the with and fatty acid synthesis was cells not with AICAR, BRCA1 silencing induced an increase in fatty acid synthesis as first shown in 1 and in cells transfected with AICAR the lipid synthesis as with cells not with AICAR 1 and However, silencing of BRCA1 in cells with AICAR increased fatty acid synthesis by as with cells transfected with and with AICAR and these AICAR was in cells the of ACCA to be to its phosphorylated BRCA1 silencing is to by an of ACCA, as in Therefore, the of in BRCA1 cells an increase of fatty acid synthesis in these ACCA its and inactive We previously identified an interaction the tandem of BRCT domains and ACCA that was by line BRCA1 mutations that affect the BRCT domains (11Magnard C. Bachelier R. Vincent A. Jaquinod M. Kieffer S. Lenoir G.M. Venezia N.D. Oncogene. 2002; 21: 6729-6739Crossref PubMed Scopus (81) Google Scholar). The of novel interaction BRCA1 and ACCA, the rate-limiting enzyme for the long chain fatty acid to the biological of the BRCA1·ACCA We to the of BRCA1 on lipid synthesis. A number of have that lipogenesis is linked to ACCA is in human breast Res. 1997; Google Scholar), and a the of ACCA sequence and breast cancer has been recently described C. M. D. K. D. C. J. P. J.P. C. Goldgar Venezia N.D. Lenoir G.M. 25: PubMed Scopus Google Scholar). tumorigenesis and FAS, the enzyme of ACCA, have been such as in a of ovarian cancer and mammary tumor in C. Res. 1996; Google Scholar, Oncogene. PubMed Scopus Google Scholar), and silencing results in and cell K. W. G. Res. 2003; Google Scholar). is in human including of and Res. 1997; Google Scholar, 2000; PubMed Scopus Google Scholar, M. I. S. H. L. K. W. G. J. 2000; PubMed Scopus Google Scholar). have associated the of these with and R. Nat. PubMed Scopus Google Scholar). The of these that of tumors associated with BRCA1 mutations D. Narod Goldgar 1994; PubMed Scopus Google Scholar). the silencing of BRCA1, line BRCA1 the BRCA1·ACCA silencing of BRCA1 may the of BRCA1 in breast and ovarian S. Lenoir G.M. L. R. Oncogene. PubMed Scopus Google Scholar). Therefore, that BRCA1 increase lipogenesis is with a role for BRCA1 in that ACCA activity may be by its interaction with BRCA1, a in which of lipid synthesis be mediated the BRCA1·ACCA an to the molecular mechanism of the BRCA1·ACCA complex and the increase of lipid we the biochemical characteristics of the BRCA1·ACCA we demonstrated that BRCA1 ACCA its BRCT domains in a phospho-dependent a of cellular the on demonstrated that BRCA1 a phosphorylated form of ACCA that to be AICAR ACCA phosphorylation at Ser79 and the antibody P-ACCA(S79) used here is to phosphorylated Therefore, the of that an ACCA region phosphorylated at at Ser79 was from in the BRCA1·ACCA ACCA is phosphorylated on Ser79 (14Winder W.W. Wilson H.A. Hardie D.G. Rasmussen B.B. Hutber C.A. Call G.B. Clayton R.D. Conley L.M. Yoon S. Zhou B. J. Appl. Physiol. 1997; 82: 219-225Crossref PubMed Scopus (61) Google Scholar, J. S. Kim K.H. J. Biol. Chem. 1994; Full Text PDF PubMed Google Scholar), results demonstrated that BRCA1 the inactive form of ACCA. be to the phosphorylated region of ACCA implicated in BRCT domains, to protein-protein (7Huyton T. Bates P.A. Zhang X. Sternberg M.J. Freemont P.S. Mutat. Res. 2000; 460: 319-332Crossref PubMed Scopus (132) Google Scholar), have recently been described as domains (8Manke I.A. Lowery D.M. Nguyen A. Yaffe M.B. Science. 2003; 302: 636-639Crossref PubMed Scopus (551) Google Scholar, 9Rodriguez M. Yu X. Chen J. Songyang Z. J. Biol. Chem. 2003; 278: 52914-52918Abstract Full Text Full Text PDF PubMed Scopus (192) Google Scholar, 10Yu X. Chini C.C. He M. Mer G. Chen J. Science. 2003; 302: 639-642Crossref PubMed Scopus (690) Google Scholar). fully we for a new function of BRCT domains, the biological of BRCA1 acts as a scaffold protein implicated in multiple cellular functions, such as transcription, DNA repair, and Cell. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). it is that the of BRCA1 in these functions is linked to the functions of the identified to (3Starita L.M. Parvin J.D. Curr. Opin. Cell Biol. 2003; 15: 345-350Crossref PubMed Scopus (191) Google Scholar, K. Y. PubMed Scopus Google Scholar). the of BRCA1 to affect lipogenesis in mammary epithelial cells is associated with its P-ACCA binding providing a new mechanism by which BRCA1 may exert tumor suppressor We for critical of the

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