Yuan Z M, Huang Y, Whang Y, Sawyers C, Weichselbaum R, Kharbanda S, Kufe D
Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
Nature. 1996 Jul 18;382(6588):272-4. doi: 10.1038/382272a0.
The c-Abl protein tyrosine kinase is activated by certain DNA-damaging agents, and its overexpression causes arrest in the G1 phase of the cell cycle by a mechanism dependent on the tumour-suppressor protein p53 (refs 2-4). Here we investigate the possible role of c-Abl in growth arrest induced by DNA damage. Transient transfection experiments using wild-type or inactivated c-Abl show that both induce expression of p21, an effector of p53, but only wild-type c-Abl downregulates the activity of the cyclin-dependent kinase Cdk2 and causes growth arrest. Exposure to ionizing radiation of cells that stably express active or inactive c-Abl is associated with induction of c-Abl/p53 complexes and p21 expression. However, cells expressing the dominant-negative c-Abl mutant and cells lacking the c-abl gene are impaired in their ability to downregulate Cdk2 or undergo G1 arrest in response to ionizing radiation. We also show that expression of c-Abl kinase in p21(-1-), but not in p53(-1-), cells results in downregulation of Cdk2. Our results suggest that c-Abl kinase contributes to the regulation of growth arrest induced by ionizing radiation by a p53-dependent, p21-independent mechanism.
c - Abl蛋白酪氨酸激酶可被某些DNA损伤剂激活，其过表达会通过一种依赖肿瘤抑制蛋白p53的机制导致细胞周期在G1期停滞（参考文献2 - 4）。在此，我们研究c - Abl在DNA损伤诱导的生长停滞中的可能作用。使用野生型或失活型c - Abl进行的瞬时转染实验表明，二者均可诱导p53效应分子p21的表达，但只有野生型c - Abl能下调细胞周期蛋白依赖性激酶Cdk2的活性并导致生长停滞。对稳定表达活性或失活型c - Abl的细胞进行电离辐射，会诱导c - Abl/p53复合物的形成以及p21的表达。然而，表达显性负性c - Abl突变体的细胞以及缺乏c - abl基因的细胞，在下调Cdk2或响应电离辐射而发生G1期停滞的能力方面存在缺陷。我们还表明，在p21基因敲除（p21(- / -)）但不是p53基因敲除（p53(- / -)）的细胞中，c - Abl激酶的表达会导致Cdk2的下调。我们的结果表明，c - Abl激酶通过一种p53依赖性、p21非依赖性机制，参与了电离辐射诱导的生长停滞的调控。
