tailieunhanh - Báo cáo khoa học: Androgen receptor function is modulated by the tissue-specific AR45 variant

A naturally occurring variant of the human androgen receptor (AR) named AR45 has been identified. It lacks the entire region encoded by exon 1 of the ARgene and is composed of the AR DNA-binding domain, hinge region and ligand-binding domain, preceded by a novel seven amino-acid long N-terminal extension. A survey of human tissues revealed that AR45 was expressed mainly in heart and skeletal muscle. In cotransfection experiments, AR45 inhibited AR function, an effect necessitating intact DNA- and ligand-binding properties. . | iFEBS Journal Androgen receptor function is modulated by the tissue-specific AR45 variant Isabelle Ahrens-Fath Oliver Politz Christoph Geserickt and Bernard Haendler Research Laboratories of Schering AG Berlin Germany Keywords androgen receptor cofactor heart prostate Correspondence B. Haendler CRBA Oncology Schering AG D-13342 Berlin Germany Fax 49 30 468 18069 Tel 49 30 468 12669 E-mail Present address Paion Research Center Berlin Germany tSpanish NationalCancer Center Madrid Spain Received 10 August 2004 revised 6 September 2004 accepted 9 September 2004 doi A naturally occurring variant of the human androgen receptor AR named AR45 has been identified. It lacks the entire region encoded by exon 1 of the AR gene and is composed of the AR DNA-binding domain hinge region and ligand-binding domain preceded by a novel seven amino-acid long N-terminal extension. A survey of human tissues revealed that AR45 was expressed mainly in heart and skeletal muscle. In cotransfection experiments AR45 inhibited AR function an effect necessitating intact DNA- and ligand-binding properties. Overexpression of AR45 reduced the proliferation rate of the androgen-dependent LNCaP cells in line with the repressive effects of AR45 on AR growth-promoting function. AR45 interacted with the AR N-terminal domain in two-hybrid assays suggesting that AR inhibition was due to the formation of AR-AR45 heterodimers. Under conditions where the transcriptional coactivator TIF2 or the oncogene b-catenin were overexpressed AR45 stimulated androgen-dependent promoters in presence of dihydrotestosterone. AR45 activity was triggered additionally by the adrenal androgen androstenedione in presence of exogenous TIF2. Altogether the data suggest an important role of AR45 in modulating AR function and add a novel level of complexity to the mode of action of androgens. The surprising finding that the human genome only codes for 20 000-25 000 genes

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