Rennie P S, Bruchovsky N, Akakura K, Goldenberg S L, Otal N, Akakura S, Wong P, Tenniswood M
Department of Cancer Endocrinology, British Columbia Cancer Agency, Vancouver, Canada.
J Steroid Biochem Mol Biol. 1994 Jul;50(1-2):31-40. doi: 10.1016/0960-0760(94)90169-4.
Progression of an androgen-dependent tumour to an androgen-independent state is characterized by the loss of apoptotic potential, a property of cells which have differentiated under the influence of androgens. In an attempt to relate progression to mechanisms of apoptotic failure, we compared the relative levels of expression of androgen receptor and TRPM-2 (clusterin) genes in androgen-dependent and -independent tumours derived from the Shionogi carcinoma. The amount of 10 kb androgen receptor mRNA in androgen-dependent and -independent cells was similar thus showing no relationship to progression. Owing to cross-hybridization of androgen receptor cDNA with non-receptor transcripts, two new androgen-repressed mRNAs (ADS31 and ADS39) were cloned. Each was found to have a 20/21 bp GC-rich region of sequence homology with the androgen receptor, implying selective conservation of a domain whose function is unknown. Sequencing results also revealed that ADS31 cDNA encodes a polypeptide identical to mouse YPT1, a ras-related GTP-binding protein. Expression of the ADS31/YPT1, ADS39 and TRPM-2 genes was sensitive to androgen withdrawal and replacement both in the parent androgen-dependent and the recurrent androgen-independent carcinomas. The uncoupling of TRPM-2 expression and apoptosis observed in androgen-independent tumour cells implies that the function of androgen receptor becomes more restricted with tumour progression. Furthermore, the fact that the expression of ADS31/YPT1 transcript becomes dominant in the advanced stages of androgen-independent growth, suggests that the mechanism of progression is subserved by duplication and possibly redundancy of alternative (signal transduction) pathways mediating tumour cell survival and growth.
雄激素依赖性肿瘤向雄激素非依赖性状态的进展，其特征是凋亡潜能丧失，这是在雄激素影响下分化的细胞所具有的一种特性。为了将进展与凋亡失败机制联系起来，我们比较了源自狮王（Shionogi）癌的雄激素依赖性和非依赖性肿瘤中雄激素受体和TRPM - 2（簇集蛋白）基因的相对表达水平。雄激素依赖性和非依赖性细胞中10 kb雄激素受体mRNA的量相似，因此与进展无关。由于雄激素受体cDNA与非受体转录本的交叉杂交，克隆了两个新的雄激素抑制mRNA（ADS31和ADS39）。发现每个都与雄激素受体有一个20/21 bp富含GC的序列同源区域，这意味着一个功能未知的结构域被选择性保留。测序结果还显示，ADS31 cDNA编码一种与小鼠YPT1相同的多肽，YPT1是一种与ras相关的GTP结合蛋白。在亲本雄激素依赖性癌和复发性雄激素非依赖性癌中，ADS31/YPT1、ADS39和TRPM - 2基因的表达对雄激素撤除和替代均敏感。在雄激素非依赖性肿瘤细胞中观察到的TRPM - 2表达与凋亡的解偶联意味着雄激素受体的功能随着肿瘤进展变得更加受限。此外，ADS31/YPT1转录本的表达在雄激素非依赖性生长的晚期占主导地位，这一事实表明进展机制是由介导肿瘤细胞存活和生长的替代（信号转导）途径的复制以及可能的冗余所维持的。
