Bai G, Kasper S, Matusik R J, Rennie P S, Moshier J A, Krongrad A
Department of Urology, University of Miami School of Medicine, Florida 33125, USA.
J Androl. 1998 Mar-Apr;19(2):127-35.
We studied the response of the human ornithine decarboxylase (ODC) promoter to androgen in human prostate cancer cell lines. In the well-differentiated, androgen-sensitive human prostate cancer line LNCaP, a genomic ODC promoter fragment that includes putative androgen response elements was suppressed by androgen. In contrast, the androgen-regulated probasin promoter was induced by androgens. The ODC promoter was also induced by cotransfected androgen receptor in the poorly differentiated, androgen-insensitive human prostate cancer cell line PPC-1. We examined the effects of cotransfected mutant androgen receptors containing the LNCaP mutation or DNA-binding mutations. All cotransfected androgen receptors switched the ODC androgen response from suppression to induction in LNCaP cells. Gel-shift and DNA footprint assays demonstrated androgen receptor binding to an ODC sequence that does not contain a consensus androgen response element. Deletion of the sequence abolished androgen suppression of the ODC promoter. We propose a model of pleiotropic gene regulation by androgen that requires a regulatory balance between androgen receptor and a transcription factor binding to the nonconsensus androgen response element.
我们研究了人鸟氨酸脱羧酶（ODC）启动子在人前列腺癌细胞系中对雄激素的反应。在分化良好、对雄激素敏感的人前列腺癌LNCaP细胞系中，包含假定雄激素反应元件的基因组ODC启动子片段受到雄激素的抑制。相反，雄激素调节的前列腺素启动子则被雄激素诱导。在分化差、对雄激素不敏感的人前列腺癌细胞系PPC-1中，共转染的雄激素受体也可诱导ODC启动子。我们检测了共转染含有LNCaP突变或DNA结合突变的突变型雄激素受体的作用。所有共转染的雄激素受体均使LNCaP细胞中ODC的雄激素反应从抑制转变为诱导。凝胶迁移和DNA足迹分析表明，雄激素受体与一个不包含共有雄激素反应元件的ODC序列结合。该序列的缺失消除了雄激素对ODC启动子的抑制作用。我们提出了一种雄激素多效性基因调控模型，该模型需要雄激素受体与结合至非共有雄激素反应元件的转录因子之间的调节平衡。
