GROWTH-FACTOR MODULATION OF P53-MEDIATED GROWTH ARREST VERSUS APOPTOSIS
GROWTH-FACTOR MODULATION OF P53-MEDIATED GROWTH ARREST VERSUS APOPTOSIS
复制标题
DOI：
10.1101/gad.9.5.600
复制
发表时间：
1995-03-01
影响因子：
10.5
通讯作者：
KASTAN, MB
中科院分区：
文献类型：
--
作者：
CANMAN, CE;GILMER, TM;KASTAN, MB
哺乳动物细胞的辐照可引起细胞周期紊乱和凋亡性细胞死亡。我们已经研究了这些生理终点的调制生长因子刺激：照射小鼠造血细胞系在白细胞介素-3（IL-3）的存在下诱导G（1）阻滞，照射在IL-3的情况下导致快速凋亡性细胞死亡。这两个终点都依赖于p53。在照射时瞬时去除IL-3导致照射细胞的克隆形成存活率降低。尽管诱导了p53和p21（WAF 1/CIP 1），但去除IL-3会导致照射细胞未能在G（1）检查点停滞，然后细胞进入S期，在那里它们经历细胞凋亡。Bcl-2、Bax或Bcl-x蛋白水平没有与尼古丁相关的变化，这些变化可以解释生长因子对G（1）阻滞与凋亡的调节。与此相反，快速p53的基础水平的gadd 45和p21（WAF 1/CIP 1）表达的独立改变与IL-3的撤退，这表明一个潜在的机制，这种调制。组成性激活的v-Src或激活的c-Raf的诱导表达的烟碱样途径抑制辐射诱导的细胞凋亡和p21（WAF 1/CIP 1）和gadd 45表达的改变。这些观察结果表明，额外的分子机制，可以促进肿瘤发生过程中的放射抗性和抗凋亡的发展，并提供了一个解释，在某些肿瘤类型中观察到的缺乏p53突变。此外，这些数据表明，在多步骤肿瘤发生过程中发生的致癌性变化可以被归类为那些增强或减少凋亡的倾向。
Irradiation of mammalian cells can cause cell cycle perturbations and apoptotic cell death. We have investigated the modulation of these physiologic end points by growth factor stimulation: irradiation of a murine hematopoietic cell line in the presence of interlekin-3 (IL-3) induces G(1) arrest, and irradiation in the absence of IL-3 results in rapid apoptotic cell death. Both of these end points are dependent on p53. Transient removal of IL-3 at the time of irradiation results in decreased clonogenic survival of irradiated cells. The removal of IL-3 results in a failure of the irradiated cells to arrest at the G(1) checkpoint, despite induction of p53 and p21(WAF1/CIP1), and then the cells enter S-phase where they undergo apoptosis. There are no cytokine-related changes in Bcl-2, Bax, or Bcl-x protein levels that could account for the modulation of G(1) arrest versus apoptosis by growth factors. In contrast, rapid p53-independent alterations of basal levels of gadd45 and p21(WAF1/CIP1) expression are linked to IL-3 withdrawal, suggesting a potential mechanism for this modulation. Constitutive activation of cytokine-like pathways with induced expression of v-Src or activated c-Raf inhibits the radiation-induced apoptosis and the alterations in p21(WAF1/CIP1) and gadd45 expression. These observations suggest additional molecular mechanisms that can contribute to the development of radioresistance and resistance to apoptosis during tumorigenesis and provide an explanation for the observed lack of p53 mutations in some tumor types. In addition, these data suggest that oncogenic changes occurring during multistep tumorigenesis could be classified as those that either enhance or decrease apoptosis tendencies.