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首页> 外文期刊>Cell cycle >Low-penetrant RB allele in small-cell cancer shows geldanamycin instability and discordant expression with mutant ras.
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Low-penetrant RB allele in small-cell cancer shows geldanamycin instability and discordant expression with mutant ras.

机译：小细胞癌中低渗透性RB等位基因显示格尔德霉素不稳定性和突变ras的表达不一致。

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Certain kindreds with low-penetrant (lp) retinoblastoma carry mutant alleles which retain partial tumor suppressor activity and we previously showed that these alleles exhibit defective, temperature-sensitive binding in yeast. To investigate the molecular basis for incomplete penetrance, we studied three recurrent lp alleles and observed approximately 50% of wildtype activity measured by (i) phosphorylation at key regulatory sites, S780, S795, S807/S811, (ii) transcriptional co-activation, and (iii) 'flat-cell' differentiation in mammalian cells in vivo. In addition, we studied a small-cell carcinoma that is homozygous for the R661W allele providing the first analysis of the effect of a naturally occurring lp allele in a human tumor. While we detected abundant expression of the R661W protein, we noted marked instability of both endogenous and recombinant R661W following treatment in vivo with the Hsp90 inhibitor, geldanamycin and stabilization of R661W following heat shock. In addition, we observed a discordant phenotype in the tumor cells with induction of p16 and loss of cyclin D1 consistent with a null RB status combined with homozygous expression of mutant ras which had not been reported previously for RB (-) small-cell cancer. These findings show that a recurrent missense lp allele retains greater functional activity in vivo than predicted from earlier in vitro assays, proposing a role for stabilizing chaperone-like activity in vivo. In addition, these data suggest that reversible protein instability and the requirement for a cooperating mutation may provide a stochastic explanation for the molecular basis of incomplete penetrance in kindreds carrying these alleles.
机译：某些具有低渗透性（lp）视网膜母细胞瘤的亲属携带保留部分抑癌活性的突变等位基因，我们之前已经证明这些等位基因在酵母中表现出有缺陷的温度敏感性结合。为了研究不完全渗透的分子基础，我们研究了三个复发性lp等位基因，并观察到约50％的野生型活性，这些活性是通过（i）关键调控位点S780，S795，S807 / S811的磷酸化，（ii）转录共激活， （iii）体内哺乳动物细胞的“扁平细胞”分化。此外，我们研究了R661W等位基因纯合的小细胞癌，首次分析了天然lp等位基因在人类肿瘤中的作用。虽然我们检测到R661W蛋白的大量表达，但我们注意到在体内用Hsp90抑制剂，格尔德霉素进行体内处理后，内源重组R661W和重组R661W均存在明显的不稳定性，并且在热激后稳定了R661W。此外，我们在肿瘤细胞中观察到不一致的表型，其中p16的诱导和细胞周期蛋白D1的缺失与RB的无效状态以及突变ras的纯合表达相符，而RB（-）小细胞癌以前没有报道。这些发现表明，与早期体外试验所预测的相比，复发性错义lp等位基因在体内保留了更大的功能活性，表明在体内具有稳定伴侣样活性的作用。此外，这些数据表明，可逆蛋白的不稳定性和协同突变的要求可能为携带这些等位基因的亲属不完全外显的分子基础提供了随机解释。

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