Pochampally R, Fodera B, Chen L, Shao W, Levine E A, Chen J
Louisiana State University Medical Center, Department of Microbiology, New Orleans, 70112, USA.
Oncogene. 1998 Nov 19;17(20):2629-36. doi: 10.1038/sj.onc.1202206.
The MDM2 oncogene product is a regulator of the p53 tumor suppressor. MDM2 is cleaved by Caspase 3 (CPP32) during apoptosis after aspartic acid-361, generating a 60 kd fragment. Here we report that human tumor cell lines often express high levels of a 60 kd MDM2 isoform (p60) in the absence of apoptosis. We demonstrate that p60 is a product of caspase cleavage of full length MDM2 after residue 361. The protease that cleaves MDM2 in non-apoptotic cells appears to be distinct from the apoptosis-specific Caspase 3, since Caspase 3 substrate poly(ADP-ribose) polymerase (PARP) is not cleaved in cells producing p60. The p60 form of MDM2 is a significant fraction of the p53-bound MDM2 protein in certain tumor cells, suggesting that it functions in the regulation of p53. p60 is also detected in breast tumors overexpressing MDM2. These observations suggest that MDM2 is regulated by caspase processing in non-apoptotic cells, and may account for the MDM2 proteins of similar mobility seen in tumors and other cell lines.
MDM2癌基因产物是p53肿瘤抑制因子的一种调节因子。在天冬氨酸-361位点之后，MDM2在凋亡过程中被半胱天冬酶3（CPP32）切割，产生一个60kd的片段。在此我们报告，人类肿瘤细胞系在不存在凋亡的情况下常常高水平表达一种60kd的MDM2同工型（p60）。我们证明p60是全长MDM2在361位残基之后经半胱天冬酶切割产生的产物。在非凋亡细胞中切割MDM2的蛋白酶似乎与凋亡特异性的半胱天冬酶3不同，因为在产生p60的细胞中半胱天冬酶3的底物聚（ADP-核糖）聚合酶（PARP）未被切割。MDM2的p60形式在某些肿瘤细胞中是与p53结合的MDM2蛋白的一个重要组分，提示它在p53的调节中发挥作用。在过表达MDM2的乳腺肿瘤中也检测到了p60。这些观察结果表明，MDM2在非凋亡细胞中受半胱天冬酶加工的调节，这可能解释了在肿瘤和其他细胞系中见到的具有相似迁移率的MDM2蛋白。
