Temperature-sensitive RB mutations linked to incomplete penetrance of familial retinoblastoma in 12 families.
Temperature-sensitive RB mutations linked to incomplete penetrance of familial retinoblastoma in 12 families.
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温度敏感的 RB 突变与 12 个家族中家族性视网膜母细胞瘤的不完全外显率相关。
DOI：
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发表时间：
1999
影响因子：
9.8
通讯作者：
Frederic J. Kaye
中科院分区：
文献类型：
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作者：
Gregory A. Otterson;Sanjay Modi;Kari Nguyen;A. Coxon;Frederic J. Kaye
视网膜母细胞瘤蛋白（RB）的肿瘤抑制活性在蛋白结合（“口袋”）结构域内编码，该结构域在所有家族性视网膜母细胞瘤病例和许多常见成人癌症中靶向突变。虽然家族性视网膜母细胞瘤是一个高度外显、隐性的肿瘤发生模式，但家族性视网膜母细胞瘤不完全外显表型的分子基础尚不明确。我们研究了三个独立的，突变的RB等位基因，存在于12个家族性视网膜母细胞瘤的表型不完全转移的kinases的种系RB口袋的结合特性。每一种都是由RB口袋结构域（命名为“delta 480”、“661 W”或“712 R”）内单个密码子的改变引起的。在相同的条件下，我们研究了野生型（WT）RB，从肺癌样品中分离的RB点突变体（706 F）和相邻的，在体外产生的点突变体（707 W）的性质。Δ 480、661 W和712 R突变体在体外缺乏口袋蛋白结合活性，但保留了WT在体内经历细胞周期蛋白介导的磷酸化的能力。当细胞在降低的温度下生长时，每个低渗透RB突变体表现出口袋蛋白结合的显著增强。相反，在该温度范围内，WT RB、706 F突变体或707 W突变体的结合活性没有变化。我们已经证明，许多家族性视网膜母细胞瘤不完全转移的家庭携带不稳定的，突变的RB等位基因与温度敏感的口袋蛋白结合活性。这些家族中肿瘤发展的可变频率可能是由于RB口袋结合活性阈值水平的可逆波动。
The tumor-suppressor activity of the retinoblastoma protein (RB) is encoded within a protein-binding ("pocket") domain that is targeted for mutations in all cases of familial retinoblastoma and in many common adult cancers. Although familial retinoblastoma is a paradigm for a highly penetrant, recessive model of tumorigenesis, the molecular basis for the phenotype of incomplete penetrance of familial retinoblastoma is undefined. We studied the RB pocket-binding properties of three independent, mutant RB alleles that are present in the germline of 12 kindreds with the phenotype of incomplete penetrance of familial retinoblastoma. Each arises from alterations of single codons within the RB pocket domain (designated "delta 480," "661W," or "712R"). Under the same conditions, we studied the properties of wild-type (WT) RB, an RB point mutant isolated from a lung carcinoma sample (706F) and an adjacent, in vitro-generated point mutant (707W). The delta 480, 661W, and 712R mutants lack pocket protein-binding activity in vitro but retain the WT ability to undergo cyclin-mediated phosphorylation in vivo. Each of the low-penetrant RB mutants exhibits marked enhancement of pocket protein binding when the cells are grown at reduced temperature. In contrast, in this temperature range, no change in binding activity is seen with WT RB, the 706F mutant, or the 707W mutant. We have demonstrated that many families with incomplete penetrance of familial retinoblastoma carry unstable, mutant RB alleles with temperature-sensitive pocket protein-binding activity. The variable frequency for tumor development in these families may result from reversible fluctuations in a threshold level of RB pocket-binding activity.
影响因子：
9.8
作者：
T. Dryja;J. Rapaport;T. L. McGee;T. Nork;Terry L. Schwartzt
通讯作者：
T. Dryja;J. Rapaport;T. L. McGee;T. Nork;Terry L. Schwartzt