Almog N, Goldfinger N, Rotter V
Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
Oncogene. 2000 Jul 13;19(30):3395-403. doi: 10.1038/sj.onc.1203673.
It is now well accepted that the p53 C-terminus plays a central role in controlling the activity of the wild-type molecule. In our previous studies, we observed that a C-terminally altered p53 protein (p53AS), generated by an alternative spliced p53 mRNA, induces an attenuated p53-dependent apoptosis, compared to that induced by the regularly spliced form (p53RS). In the present study we analysed the interrelationships between these two physiological variants of wild-type p53, and found that in cells co-expressing both forms, in contrast to the expected additive effect on the induction of apoptosis, p53AS inhibits apoptosis induced by p53RS. This inhibitory effect is specific for p53-dependent apoptosis and was not evident in a p53-independent apoptotic pathway induced by growth factor deprivation. Furthermore, the expression of p53AS in transiently transfected cells caused both inhibition of apoptosis and inhibition of the p53RS-dependent transactivation of a number of p53 target genes. These results suggest that expression of an alternatively spliced p53 form may serve as an additional level in controlling the complexity of p53 function by the C-terminal domain.
现在人们普遍认为，p53的C末端在控制野生型分子的活性中起着核心作用。在我们之前的研究中，我们观察到，由选择性剪接的p53 mRNA产生的C末端改变的p53蛋白（p53AS）与正常剪接形式（p53RS）诱导的相比，诱导的p53依赖性凋亡减弱。在本研究中，我们分析了野生型p53的这两种生理变体之间的相互关系，发现与预期的对凋亡诱导的加性效应相反，在共表达这两种形式的细胞中，p53AS抑制p53RS诱导的凋亡。这种抑制作用对p53依赖性凋亡具有特异性，在生长因子剥夺诱导的p53非依赖性凋亡途径中不明显。此外，在瞬时转染细胞中p53AS的表达导致凋亡抑制以及对多个p53靶基因的p53RS依赖性反式激活的抑制。这些结果表明，选择性剪接的p53形式的表达可能作为通过C末端结构域控制p53功能复杂性的额外水平。
