NCOA3 식별자 별칭 NCOA3 외부 ID OMIM : 601937 MGI : 1276535 HomoloGene : 4764 GeneCard : NCOA3 직교체 종 인간 마우스 엔트레스 앙상블 유니프로트 RefSeq(mRNA) RefSeq(단백질) 위치(UCSC) Chr 20: 47.5 – 47.66Mb Chr 2: 165.99 – 166.07Mb PubMed 검색[3] [4] 위키다타
NCOA3 라고도 알려진 핵수용체 공동활성화기 3은 인간에서 NCOA3 유전자 에 의해 암호화된 단백질 이다.[5] [6] NCOA3는 '유방 1에서 증폭'(AIB1)이나 스테로이드 수용체 공동활성화제-3(SRC-3 ) 또는 갑상선 호르몬 수용체 활성제 1(TRAM-1)이라고도 불린다.
함수 NCOA3는 여러 개의 핵수용체 상호 작용 영역과 내인 히스톤 아세틸전달효소 활동을 포함하는 전사적 공동활성제 단백질이다. NCOA3는 리간드 활성 핵 수용체에 의해 DNA 촉진 현장에 채용된다. 다시, NCOA3는 히스톤 을 아틸레이트하여 다운스트림 DNA를 전사하기 쉽게 만든다. 따라서, NCOA3는 유전자 발현의 상향 조절에서 핵 수용체 를 지원한다.[7] [8]
임상적 유의성 PAX2 대 AIB-1 단백질 표현 비율은 유방암 치료 에서 타목시펜 의 효과를 예측할 수 있다.[9] [10]
몇 가지 분자 메커니즘은 내분비 치료 저항(그림에서 제외됨)에 NCOA3(AIB1)을 포함한다. 신호 경로 또는 돌연변이(즉, HER2/neu 과다압박, PIK3CA (PI3K)에서 돌연변이를 활성화하고, ERK 및/또는 PIK3의 지속적인 활성화를 유도하는 원종 제3종 tyrosine-단백질 kinase Src 등)의 돌연변이를 활성화하는 것. CA/AKT 키나제 경로는 한 손으로는 향상된 AIB1 전사적 공동 활성화 용량을, [11] [12] 두 조건 모두에서 에스트로겐 수용체(ER) 복합형성의 평형은 전사적으로 활성하는 복합체 쪽으로 대체되어 타목시펜 이나 풀베스트런트 (선택적 에스트로겐 수용체 조절기 )와 같은 항에스트로겐성 약물에 의한 억제에 대항한다. 그 결과는 에스트로겐에 민감한 유전자 전사의 복원과 암의 진행 및/또는 재발 촉진이다.
특히 AIB1과 HER2/neu 의 동반성 과다압박으로 진단된 종양은 타목시펜요법으로 다른 모든 환자를 합친 것보다 결과가 더 나쁘다.[13] 또한 내분비 치료로 치료된 발진 유방암의 휴면 종양 세포는 키나제 신호 전달 경로를 변경하고 궁극적으로 AIB1 종양 기능을 강화하는 돌연변이를 시간이 지남에 따라 획득할 수 있다. 또한 에스트로겐 수용체-PAX2 복합체는 HER2/neu 발현을 억제하지만, PAX2 발현 상실로 인해 de novo HER2/neu 발현이 발생하여 내분비 치료 저항성이 생기고 재발할 수 있다.[14]
AIB1 의존적 항에스트로겐 치료 저항성 메커니즘 상호작용 핵수용체 공동활성화기 3은 다음과 상호작용 하는 것으로 나타났다.
참조 ^ a b c GRCh38: 앙상블 릴리스 89: ENSG00000124151 - 앙상블 , 2017년 5월^ a b c GRCm38: 앙상블 릴리스 89: ENSMUSG000027678 - 앙상블 , 2017년 5월^ "Human PubMed Reference:" . National Center for Biotechnology Information, U.S. National Library of Medicine .^ "Mouse PubMed Reference:" . National Center for Biotechnology Information, U.S. National Library of Medicine .^ Anzick SL, Kononen J, Walker RL, Azorsa DO, Tanner MM, Guan XY, Sauter G, Kallioniemi OP, Trent JM, Meltzer PS (August 1997). "AIB1, a steroid receptor coactivator amplified in breast and ovarian cancer" . Science . 277 (5328): 965–8. doi :10.1126/science.277.5328.965 . PMID 9252329 . ^ Takeshita A, Cardona GR, Koibuchi N, Suen CS, Chin WW (October 1997). "TRAM-1, A novel 160-kDa thyroid hormone receptor activator molecule, exhibits distinct properties from steroid receptor coactivator-1" . J. Biol. Chem . 272 (44): 27629–34. doi :10.1074/jbc.272.44.27629 PMID 9346901 . ^ Anzick SL, Kononen J, Walker RL, Azorsa DO, Tanner MM, Guan XY, Sauter G, Kallioniemi OP, Trent JM, Meltzer PS (1997). "AIB1, a steroid receptor coactivator amplified in breast and ovarian cancer" . Science . 277 (5328): 965–8. doi :10.1126/science.277.5328.965 . PMID 9252329 . ^ Takeshita A, Cardona GR, Koibuchi N, Suen CS, Chin WW (1997). "TRAM-1, A novel 160-kDa thyroid hormone receptor activator molecule, exhibits distinct properties from steroid receptor coactivator-1" . J Biol Chem . 272 (44): 27629–34. doi :10.1074/jbc.272.44.27629 PMID 9346901 . ^ "Study sheds new light on tamoxifen resistance" . Cordis News . Cordis. 2008-11-13. Retrieved 2008-11-14 .^ Hurtado A, Holmes KA, Geistlinger TR, Hutcheson IR, Nicholson RI, Brown M, et al. (December 2008). "Regulation of ERBB2 by oestrogen receptor-PAX2 determines response to tamoxifen" . Nature . 456 (7222): 663–6. Bibcode :2008Natur.456..663H . doi :10.1038/nature07483 . PMC 2920208 PMID 19005469 . ^ Font de Mora J, Brown M (July 2000). "AIB1 is a conduit for kinase-mediated growth factor signaling to the estrogen receptor" . Molecular and Cellular Biology . 20 (14): 5041–7. doi :10.1128/MCB.20.14.5041-5047.2000 . PMC 85954 PMID 10866661 . ^ Ferrero M, Avivar A, García-Macías MC, Font de Mora J (July 2008). "Phosphoinositide 3-kinase/AKT signaling can promote AIB1 stability independently of GSK3 phosphorylation" . Cancer Research . 68 (13): 5450–9. doi :10.1158/0008-5472.CAN-07-6433 PMID 18593948 . ^ Osborne CK, Bardou V, Hopp TA, Chamness GC, Hilsenbeck SG, Fuqua SA, et al. (March 2003). "Role of the estrogen receptor coactivator AIB1 (SRC-3) and HER-2/neu in tamoxifen resistance in breast cancer" . Journal of the National Cancer Institute . 95 (5): 353–61. doi :10.1093/jnci/95.5.353 PMID 12618500 . ^ Hurtado A, Holmes KA, Geistlinger TR, Hutcheson IR, Nicholson RI, Brown M, et al. (December 2008). "Regulation of ERBB2 by oestrogen receptor-PAX2 determines response to tamoxifen" . Nature . 456 (7222): 663–6. Bibcode :2008Natur.456..663H . doi :10.1038/nature07483 . PMC 2920208 PMID 19005469 . ^ Tan JA, Hall SH, Petrusz P, French FS (September 2000). "Thyroid receptor activator molecule, TRAM-1, is an androgen receptor coactivator" . Endocrinology . 141 (9): 3440–50. doi :10.1210/endo.141.9.7680 PMID 10965917 . ^ Gnanapragasam VJ, Leung HY, Pulimood AS, Neal DE, Robson CN (December 2001). "Expression of RAC 3, a steroid hormone receptor co-activator in prostate cancer" . Br. J. Cancer . 85 (12): 1928–36. doi :10.1054/bjoc.2001.2179 . PMC 2364015 PMID 11747336 . ^ Wang Q, Udayakumar TS, Vasaitis TS, Brodie AM, Fondell JD (April 2004). "Mechanistic relationship between androgen receptor polyglutamine tract truncation and androgen-dependent transcriptional hyperactivity in prostate cancer cells" . J. Biol. Chem . 279 (17): 17319–28. doi :10.1074/jbc.M400970200 PMID 14966121 . ^ a b c d Wu RC, Qin J, Hashimoto Y, Wong J, Xu J, Tsai SY, Tsai MJ, O'Malley BW (May 2002). "Regulation of SRC-3 (pCIP/ACTR/AIB-1/RAC-3/TRAM-1) Coactivator activity by I kappa B kinase" . Mol. Cell. Biol . 22 (10): 3549–61. doi :10.1128/MCB.22.10.3549-3561.2002 . PMC 133790 PMID 11971985 . ^ Naltner A, Wert S, Whitsett JA, Yan C (December 2000). "Temporal/spatial expression of nuclear receptor coactivators in the mouse lung". Am. J. Physiol. Lung Cell Mol. Physiol . 279 (6): L1066-74. doi :10.1152/ajplung.2000.279.6.l1066 . PMID 11076796 . ^ a b c Watanabe M, Yanagisawa J, Kitagawa H, Takeyama K, Ogawa S, Arao Y, Suzawa M, Kobayashi Y, Yano T, Yoshikawa H, Masuhiro Y, Kato S (March 2001). "A subfamily of RNA-binding DEAD-box proteins acts as an estrogen receptor alpha coactivator through the N-terminal activation domain (AF-1) with an RNA coactivator, SRA" . EMBO J . 20 (6): 1341–52. doi :10.1093/emboj/20.6.1341 . PMC 145523 PMID 11250900 . ^ a b Wong CW, Komm B, Cheskis BJ (June 2001). "Structure-function evaluation of ER alpha and beta interplay with SRC family coactivators. ER selective ligands". Biochemistry . 40 (23): 6756–65. doi :10.1021/bi010379h . PMID 11389589 . ^ Tikkanen MK, Carter DJ, Harris AM, Le HM, Azorsa DO, Meltzer PS, Murdoch FE (November 2000). "Endogenously expressed estrogen receptor and coactivator AIB1 interact in MCF-7 human breast cancer cells" . Proc. Natl. Acad. Sci. U.S.A . 97 (23): 12536–40. Bibcode :2000PNAS...9712536T . doi :10.1073/pnas.220427297 PMC 18799 PMID 11050174 . ^ Leo C, Li H, Chen JD (February 2000). "Differential mechanisms of nuclear receptor regulation by receptor-associated coactivator 3" . J. Biol. Chem . 275 (8): 5976–82. doi :10.1074/jbc.275.8.5976 PMID 10681591 . ^ Hsiao PW, Fryer CJ, Trotter KW, Wang W, Archer TK (September 2003). "BAF60a mediates critical interactions between nuclear receptors and the BRG1 chromatin-remodeling complex for transactivation" . Mol. Cell. Biol . 23 (17): 6210–20. doi :10.1128/MCB.23.17.6210-6220.2003 . PMC 180928 PMID 12917342 . ^ Zilliacus J, Holter E, Wakui H, Tazawa H, Treuter E, Gustafsson JA (April 2001). "Regulation of glucocorticoid receptor activity by 14--3-3-dependent intracellular relocalization of the corepressor RIP140" . Mol. Endocrinol . 15 (4): 501–11. doi :10.1210/mend.15.4.0624 PMID 11266503 . ^ Kodera Y, Takeyama K, Murayama A, Suzawa M, Masuhiro Y, Kato S (October 2000). "Ligand type-specific interactions of peroxisome proliferator-activated receptor gamma with transcriptional coactivators" . J. Biol. Chem . 275 (43): 33201–4. doi :10.1074/jbc.C000517200 PMID 10944516 . ^ Chen H, Lin RJ, Schiltz RL, Chakravarti D, Nash A, Nagy L, Privalsky ML, Nakatani Y, Evans RM (August 1997). "Nuclear receptor coactivator ACTR is a novel histone acetyltransferase and forms a multimeric activation complex with P/CAF and CBP/p300" . Cell . 90 (3): 569–80. doi :10.1016/S0092-8674(00)80516-4 PMID 9267036 . S2CID 15284825 . ^ Lee WY, Noy N (February 2002). "Interactions of RXR with coactivators are differentially mediated by helix 11 of the receptor's ligand binding domain". Biochemistry . 41 (8): 2500–8. doi :10.1021/bi011764+ . PMID 11851396 .
외부 링크 추가 읽기 Liao L, Kuang SQ, Yuan Y, Gonzalez SM, O'Malley BW, Xu J (2003). "Molecular structure and biological function of the cancer-amplified nuclear receptor coactivator SRC-3/AIB1". J. Steroid Biochem. Mol. Biol . 83 (1–5): 3–14. doi :10.1016/S0960-0760(02)00254-6 . PMID 12650696 . S2CID 40981759 . Liu F, Ventura F, Doody J, Massagué J (1995). "Human type II receptor for bone morphogenic proteins (BMPs): extension of the two-kinase receptor model to the BMPs" . Mol. Cell. Biol . 15 (7): 3479–86. doi :10.1128/mcb.15.7.3479 . PMC 230584 PMID 7791754 . Guan XY, Xu J, Anzick SL, Zhang H, Trent JM, Meltzer PS (1996). "Hybrid selection of transcribed sequences from microdissected DNA: isolation of genes within amplified region at 20q11-q13.2 in breast cancer". Cancer Res . 56 (15): 3446–50. PMID 8758910 . Bonaldo MF, Lennon G, Soares MB (1997). "Normalization and subtraction: two approaches to facilitate gene discovery" . Genome Res . 6 (9): 791–806. doi :10.1101/gr.6.9.791 PMID 8889548 . Margolis RL, Abraham MR, Gatchell SB, Li SH, Kidwai AS, Breschel TS, Stine OC, Callahan C, McInnis MG, Ross CA (1997). "cDNAs with long CAG trinucleotide repeats from human brain". Hum. Genet . 100 (1): 114–22. doi :10.1007/s004390050476 . PMID 9225980 . S2CID 25999127 . Li H, Gomes PJ, Chen JD (1997). "RAC3, a steroid/nuclear receptor-associated coactivator that is related to SRC-1 and TIF2" . Proc. Natl. Acad. Sci. U.S.A . 94 (16): 8479–84. Bibcode :1997PNAS...94.8479L . doi :10.1073/pnas.94.16.8479 PMC 22964 PMID 9238002 . Anzick SL, Kononen J, Walker RL, Azorsa DO, Tanner MM, Guan XY, Sauter G, Kallioniemi OP, Trent JM, Meltzer PS (1997). "AIB1, a steroid receptor coactivator amplified in breast and ovarian cancer" . Science . 277 (5328): 965–8. doi :10.1126/science.277.5328.965 . PMID 9252329 . Chen H, Lin RJ, Schiltz RL, Chakravarti D, Nash A, Nagy L, Privalsky ML, Nakatani Y, Evans RM (1997). "Nuclear receptor coactivator ACTR is a novel histone acetyltransferase and forms a multimeric activation complex with P/CAF and CBP/p300" . Cell . 90 (3): 569–80. doi :10.1016/S0092-8674(00)80516-4 PMID 9267036 . S2CID 15284825 . Takeshita A, Cardona GR, Koibuchi N, Suen CS, Chin WW (1997). "TRAM-1, A novel 160-kDa thyroid hormone receptor activator molecule, exhibits distinct properties from steroid receptor coactivator-1" . J. Biol. Chem . 272 (44): 27629–34. doi :10.1074/jbc.272.44.27629 PMID 9346901 . Korzus E, Torchia J, Rose DW, Xu L, Kurokawa R, McInerney EM, Mullen TM, Glass CK, Rosenfeld MG (1998). "Transcription factor-specific requirements for coactivators and their acetyltransferase functions". Science . 279 (5351): 703–7. Bibcode :1998Sci...279..703K . doi :10.1126/science.279.5351.703 . PMID 9445475 . Shirazi SK, Bober MA, Coetzee GA (1998). "Polymorphic exonic CAG microsatellites in the gene amplified in breast cancer (AIB1 gene)". Clin. Genet . 54 (1): 102–3. doi :10.1111/j.1399-0004.1998.tb03704.x . PMID 9727751 . S2CID 1315265 . Wang JC, Stafford JM, Granner DK (1998). "SRC-1 and GRIP1 coactivate transcription with hepatocyte nuclear factor 4" . J. Biol. Chem . 273 (47): 30847–50. doi :10.1074/jbc.273.47.30847 PMC 3968904 PMID 9812974 . Zwijsen RM, Buckle RS, Hijmans EM, Loomans CJ, Bernards R (1999). "Ligand-independent recruitment of steroid receptor coactivators to estrogen receptor by cyclin D1" . Genes Dev . 12 (22): 3488–98. doi :10.1101/gad.12.22.3488 . PMC 317237 PMID 9832502 . Chen H, Lin RJ, Xie W, Wilpitz D, Evans RM (1999). "Regulation of hormone-induced histone hyperacetylation and gene activation via acetylation of an acetylase" . Cell . 98 (5): 675–86. doi :10.1016/S0092-8674(00)80054-9 PMID 10490106 . S2CID 14697597 . Ebisawa T, Tada K, Kitajima I, Tojo K, Sampath TK, Kawabata M, Miyazono K, Imamura T (2000). "Characterization of bone morphogenetic protein-6 signaling pathways in osteoblast differentiation". J. Cell Sci . 112 (20): 3519–27. doi :10.1242/jcs.112.20.3519 . PMID 10504300 . Xie W, Hong H, Yang NN, Lin RJ, Simon CM, Stallcup MR, Evans RM (2000). "Constitutive activation of transcription and binding of coactivator by estrogen-related receptors 1 and 2" . Mol. Endocrinol . 13 (12): 2151–62. doi :10.1210/me.13.12.2151 PMID 10598588 . Pao GM, Janknecht R, Ruffner H, Hunter T, Verma IM (2000). "CBP/p300 interact with and function as transcriptional coactivators of BRCA1" . Proc. Natl. Acad. Sci. U.S.A . 97 (3): 1020–5. Bibcode :2000PNAS...97.1020P . doi :10.1073/pnas.97.3.1020 PMC 15508 PMID 10655477 . Leo C, Li H, Chen JD (2000). "Differential mechanisms of nuclear receptor regulation by receptor-associated coactivator 3" . J. Biol. Chem . 275 (8): 5976–82. doi :10.1074/jbc.275.8.5976 PMID 10681591 . Font de Mora J, Brown M (2000). "AIB1 is a conduit for kinase-mediated growth factor signaling to the estrogen receptor" . Mol. Cell. Biol . 20 (14): 5041–7. doi :10.1128/MCB.20.14.5041-5047.2000 . PMC 85954 PMID 10866661 . Tan JA, Hall SH, Petrusz P, French FS (2000). "Thyroid receptor activator molecule, TRAM-1, is an androgen receptor coactivator" . Endocrinology . 141 (9): 3440–50. doi :10.1210/endo.141.9.7680 PMID 10965917 .
PDB 갤러리
1kbh : 핵수용체 공동활성화기 CBP와 ACTR의 상호작용에서의 상호 시너지 폴딩
