Ras induces anchorage-independent growth by subverting multiple adhesion-regulated cell cycle events.
Ras induces anchorage-independent growth by subverting multiple adhesion-regulated cell cycle events.
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Ras 通过破坏多种粘附调节的细胞周期事件来诱导贴壁依赖性生长。
DOI：
10.1128/mcb.16.7.3370
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发表时间：
1996
影响因子：
5.3
通讯作者：
Krauss,RS
中科院分区：
文献类型：
--
作者：
Kang,JS;Krauss,RS
锚定非依赖性生长是转化细胞的一个标志，但对这种现象背后的分子机制知之甚少。我们在这里描述的细胞周期控制的锚定非依赖性生长的therasoncogene诱导的研究，与使用的体细胞突变成纤维细胞系（ER-1-2），是专门缺陷的癌基因介导的，锚定非依赖性生长。对照、未转化的PKC 3-F4细胞和ER-1-2细胞不能在半固体培养基中增殖。三个重要的细胞周期事件依赖于这些细胞对基质的粘附：视网膜母细胞瘤蛋白pRB的磷酸化;细胞周期蛋白E依赖性激酶活性;和细胞周期蛋白A表达。表达ras的PKC 3-F4细胞（PKC 3-F4/ras细胞）在非粘附培养物中增殖，并且这三个事件中的每一个都在PKC 3-F4/ras细胞中不存在粘附的情况下发生。因此，rascan超越细胞周期进程所必需的细胞功能的粘附要求。表达ras的ER-1-2细胞（ER-1-2/ras细胞）在不存在粘附的情况下具有pRB的过度磷酸化形式和细胞周期蛋白E依赖性激酶活性，但对于细胞周期蛋白A的表达保持粘附依赖性。因此，pRB磷酸化和细胞周期蛋白E依赖性激酶活性的粘附依赖性与细胞周期蛋白A表达的粘附依赖性是分离的。此外，细胞周期蛋白A的异位表达足以拯救ER-1-2/ras细胞的锚定非依赖性生长，但不诱导PKC 3-F4或ER-1-2细胞的锚定非依赖性生长。然而，与pRB磷酸化和细胞周期蛋白E依赖性激酶活性一样，与异位表达的细胞周期蛋白A相关的激酶活性依赖于细胞粘附，并且这种依赖性被byras所克服，因此，byras诱导锚定非依赖性生长可能涉及多种信号，这些信号导致细胞周期蛋白A的表达和G1细胞周期蛋白依赖性激酶活性在细胞粘附缺乏的情况下的激活。
Anchorage-independent growth is a hallmark of transformed cells, but little is known of the molecular mechanisms that underlie this phenomenon. We describe here studies of cell cycle control of anchorage-independent growth induced by therasoncogene, with the use of a somatic cell mutant fibroblast line (ER-1-2) that is specifically defective in oncogene-mediated, anchorage-independent growth. Control, nontransformed PKC3-F4 cells and ER-1-2 cells cannot proliferate in semisolid medium. Three important cell cycle events are dependent on adhesion of these cells to a substratum: phosphorylation of the retinoblastoma protein, pRB; cyclin E-dependent kinase activity; and cyclin A expression. PKC3-F4 cells that expressras(PKC3-F4/rascells) proliferate in nonadherent cultures, and each of these three events occurs in the absence of adhesion in PKC3-F4/rascells. Thus,rascan override the adhesion requirement of cellular functions that are necessary for cell cycle progression. ER-1-2 cells that expressras(ER-1-2/rascells) possess hyperphosphorylated forms of pRB and cyclin E-dependent kinase activity in the absence of adhesion but remain adhesion dependent for expression of cyclin A. The adhesion dependence of pRB phosphorylation and cyclin E-dependent kinase activity is therefore dissociable from the adhesion dependence of cyclin A expression. Furthermore, ectopic expression of cyclin A is sufficient to rescue anchorage-independent growth of ER-1-2/rascells but does not induce anchorage-independent growth of PKC3-F4 or ER-1-2 cells. However, like pRB phosphorylation and cyclin E-dependent kinase activity, the kinase activity associated with ectopically expressed cyclin A is dependent on cell adhesion, and this dependence is overcome byras.Thus, the induction of anchorage-independent growth byrasmay involve multiple signals that lead to both expression of cyclin A and activation of G1cyclin-dependent kinase activities in the absence of cell adhesion.