BCAS2的雙重功能之研究：為抑癌基因p53的新穎負調控者及核接受體的共同轉錄因子

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BCAS2的雙重功能之研究：為抑癌基因p53的新穎負調控者及核接受體的共同轉錄因子

The Dual Roles of BCAS2 as a Novel Negative Regulator of the p53 Tumor Suppressor and a Transcription Cofactor of Nuclear Receptor

張紘瑋 , Masters　　Advisor：陳小梨　　

英文

p53負調控者； BCAS2 ；雄激素受體；細胞凋亡； p21 ； p53 negative regulator ； BCAS2 ； androgen receptor ； apoptosis ； p21 ； transcription cofactor

Abstract │ Reference (93) │ Altmetrics

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A nuclear protein which is encoded by a novel gene, breast cancer amplified sequence 2 (BCAS2), has been identified by applying the androgen receptor (AR) as a bait to prey a human HeLa MATCHMAKER cDNA library in a yeast-two hybrid screening system. Recent reports from the other groups show that BCAS2 is mapped on the chromosome 1p13.3-21 region, and also can enhance estrogen receptor (ER)-mediated transcription activity and regulate pro-apoptotic activity. 
In this study, for characterization and identification of the functions of BCAS2, the GST pull-down assay was conducted to analyze the BCAS2 interacting proteins from nuclear extracts. Here, we first demonstrated that BCAS2 can directly interact with p53 in nucleus by in vitro GST pull-down assay, and the reciprocal IP-Western. Additionally, BCAS2 overexpression can lead to repress the activities of p53 by p21 promoter reporter assay, and can block p53-inducible p21 protein expression when treated with doxorubicin. When silencing of BCAS2 by siRNA, it can enhance the p53 transcriptional activities resulting in the increase of p21 and BAX protein expression, and also can cause the decrease of cell growth and increase cell death both in MCF-7 and LNCaP cells those containing wild type p53. It suggests that BCAS2 may play a role as a negative regulator of p53.

On the other hand, in our investigation BCAS2 also can bind to androgen receptor and can enhance AR-driven prostate specific antigen (PSA) promoter activity which is a biomarker to monitor prostate cancer. The reporter assay and RT-PCR results revealed that the decrease of endogenous BCAS2 expression caused by siBCAS2 decreased the AR-mediated PSA promoter activity and PSA mRNA expression in LNCaP cells. Additionally AR and BCAS2 can co-localize on the AR response elements within PSA promoter by the chromatin IP assay. BCAS2 is also as a transcription cofactor to enhance AR-mediated gene expression in prostate cancer cells. In this study, we demonstrate that BCAS2 has dual roles: one is a coactivator of the nuclear receptor and the other the inhibitor of p53.

Reference ( 93 ) 〈TOP〉

Alimirah F, Panchanathan R, Chen J, Zhang X, Ho SM, Choubey D. (2007). Expression of androgen receptor is negatively regulated by p53. Neoplasia. 9, 1152-9.
連結：
Almeida A, Muleris M, Dutrillaux B, Malfoy B. (1994). The insulin-like growth factor I receptor gene is the target for the 15q26 amplicon in breast cancer. Genes Chromosomes Cancer. 11, 63-65.
連結：
Aylon Y, Oren M. (2007). Living with p53, dying of p53. Cell. 130, 597-600.
連結：
Berns EM, Foekens JA, van Staveren IL, van Putten WL, de Koning HY, Portengen H, Klijn JG. (1995). Oncogene amplification and prognosis in breast cancer: relationship with systemic treatment. Gene 159, 11-18.
連結：
Beck BD, Park SJ, Lee YJ, Roman Y, Hromas RA, Lee SH. (2008). Human Pso4 is a metnase (SETMAR)-binding partner that regulates metnase function in DNA repair. J Biol Chem. 283, 9023-30
連結：

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