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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Distinct and nonoverlapping roles for pRB and cyclin D:cyclin-dependent kinases 4/6 activity in melanocyte survival
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Distinct and nonoverlapping roles for pRB and cyclin D:cyclin-dependent kinases 4/6 activity in melanocyte survival

机译：黑色素细胞存活中pRB和细胞周期蛋白D：细胞周期蛋白依赖性激酶4/6活性的不同和不重叠的作用

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摘要

Deregulation of the p16~(INK4a)-cyclin D:cyclin-dependent kinases (cdk)4/6-retinoblastoma (pRB) pathway is a common paradigm in the oncogenic transformation of human cells and suggests that this pathway functions linearly in malignant transformation. However, it is not understood why p16~(INK4a) and cyclin D:cdk4/6 mutations are disproportionately more common than the rare genetic event of RB inactivation in human malignancies such as melanoma. To belter understand how these complexes contribute to altered tissue homeostasis, we blocked cdk4/6 activation and acutely inactivated Rb by conditional mutagenesis during mouse hair follicle cycling. Inhibition of cdk4/6 in the skin by subcutaneous administration of a membrane-transducible TAT-p16~(INK4a) protein completely blocked hair follicle growth and differentiation. In contrast, acute disruption of Rb in the skin of homozygous Rb~(LoxP/LoxP) mice via subcutaneous administration of TAT-Cre re-combinase failed to affect hair growth. However, loss of Rb resulted in severe depigmentation of hair follicles. Further analysis of follicular melanocytes in vivo and in primary cell culture demonstrated that pRB plays a cell-autonomous role in melanocyte survival. Moreover, functional inactivation of all three Rb family members (Rb, p107, and p130) in primary melanocytes by treatment with a transducible TAT-E1A protein did not rescue the apoptotic phenotype. These findings suggest that deregulated cyclin D:cdk4/6 complexes and pRB perform nonoverlapping functions in vivo and provide a cellular mechanism that accounts for the low incidence of RB inactivation in cancers such as melanoma.
机译：p16〜（INK4a）-细胞周期蛋白D：细胞周期蛋白依赖性激酶（cdk）4 / 6-视网膜母细胞瘤（pRB）通路的失调是人类细胞致癌转化的常见范例，表明该途径在恶性转化中呈线性作用。然而，尚不清楚为什么在人类恶性肿瘤如黑色素瘤中，p16〜（INK4a）和细胞周期蛋白D：cdk4 / 6突变比RB失活的罕见遗传事件不成比例地更为普遍。为了了解这些复合物如何导致组织动态平衡改变，我们在小鼠毛囊循环过程中通过条件诱变来阻断cdk4 / 6激活和急性灭活的Rb。皮下注射可转导的TAT-p16〜（INK4a）蛋白可抑制皮肤中cdk4 / 6，从而完全阻断毛囊的生长和分化。相反，通过皮下施用TAT-Cre重组酶对纯合Rb〜（LoxP / LoxP）小鼠皮肤中Rb的急性破坏不能影响头发的生长。但是，Rb的损失会导致毛囊严重脱色。体内和原代细胞培养物中卵泡黑素细胞的进一步分析表明，pRB在黑素细胞存活中起细胞自主作用。此外，通过用可转导的TAT-E1A蛋白处理，原代黑素细胞中所有三个Rb家族成员（Rb，p107和p130）的功能失活均不能挽救细胞凋亡表型。这些发现表明，解除调节的细胞周期蛋白D：cdk4 / 6复合物和pRB在体内具有不重叠的功能，并提供了一种细胞机制，说明癌症（例如黑素瘤）中RB失活的发生率低。

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