Senescence of human fibroblasts induced by oncogenic Raf
Senescence of human fibroblasts induced by oncogenic Raf
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DOI：
10.1101/gad.12.19.2997
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发表时间：
1998-10-01
影响因子：
10.5
通讯作者：
Bishop, JM
中科院分区：
文献类型：
--
作者：
Zhu, JY;Woods, D;Bishop, JM
癌基因RAS和RAP被认为是肿瘤转化的因子。然而，在正常细胞中，这些基因可能具有与致癌转化相反的作用，例如细胞分裂周期的停滞，细胞分化的诱导和细胞凋亡。最近的研究表明，RAS在正常小鼠和人成纤维细胞中促进增殖停滞和衰老。由于Raf/MEK/MAP激酶信号级联是Ras蛋白信号传导的关键效应子，我们检测了Raf-1的条件活性形式在人细胞中引起细胞周期停滞和衰老的能力。Raf-1在非永生化人肺成纤维细胞（IMR-90）中的激活导致细胞增殖的迅速和不可逆的停滞以及衰老的过早发生。伴随着细胞周期停滞的发生，我们观察到细胞周期蛋白依赖性激酶（CDK）抑制剂p21（Cip 1）和p16（Ink 4a）的诱导。通过使用HPV 16的E6癌蛋白来消融p53和p21（Cip 1）表达表明，Raf-induced细胞周期停滞或衰老不需要这些蛋白的表达。此外，细胞周期停滞和衰老引起IMR-90细胞的异位表达p16（Ink 4a）单独。Raf/MEK/MAP激酶级联的药理学抑制防止Raf诱导p16（Ink 4a），并且还防止Raf诱导的衰老。我们的结论是，激酶级联启动Raf可以调节p16（Ink 4a）的表达和增殖停滞和衰老，随后。当MAP激酶信号级联反应不适当地活跃时，衰老的诱导可以提供对肿瘤转化的防御。
The oncogenes RAS and RAP came to view as agents of neoplastic transformation. However, in normal cells, these genes can have effects that run counter to oncogenic transformation, such as arrest of the cell division cycle, induction of cell differentiation, and apoptosis. Recent work has demonstrated that RAS elicits proliferative arrest and senescence in normal mouse and human fibroblasts. Because the Raf/MEK/MAP kinase signaling cascade is a key effector of signaling from Ras proteins, we examined the ability of conditionally active forms of Raf-1 to elicit cell cycle arrest and senescence in human cells. Activation of Raf-1 in nonimmortalized human lung fibroblasts (IMR-90) led to the prompt and irreversible arrest of cellular proliferation and the premature onset of senescence. Concomitant with the onset of cell cycle arrest, we observed the induction of the cyclin-dependent kinase (CDK) inhibitors p21(Cip1) and p16(Ink4a). Ablation of p53 and p21(Cip1) expression by use of the E6 oncoprotein of HPV16 demonstrated that expression of these proteins was not required for Raf-induced cell cycle arrest or senescence. Furthermore, cell cycle arrest and senescence were elicited in IMR-90 cells by the ectopic expression of p16(Ink4a) alone. Pharmacological inhibition of the Raf/MEK/MAP kinase cascade prevented Raf from inducing p16(Ink4a) and also prevented Raf-induced senescence. We conclude that the kinase cascade initiated by Raf can regulate the expression of p16(Ink4a) and the proliferative arrest and senescence that follows. Induction of senescence may provide a defense against neoplastic transformation when the MAP kinase signaling cascade is inappropriately active.