Dubs-Poterszman M C, Tocque B, Wasylyk B
Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France.
Oncogene. 1995 Dec 7;11(11):2445-9.
The p53 tumour-suppressor guards the genome in response to genotoxic stress by transcriptional regulation of genes involved in cell-cycle control, DNA replication, repair and apoptosis such as p21, GADD45, bax and mdm2 (Cox and Lane, 1995). Mdm2 is classically considered to be an inhibitor of p53, that forms an auto-regulatory loop (Momand et al., 1992; Oliner et al., 1993; Wu et al., 1993; Chen et al., 1994; Chen and Levine, 1995). It immortalises cells containing wild type p53 and transforms them together with Ras (Finlay, 1993). We show that, in the absence of p53, mdm2 confers a growth advantage to cells (i.e. "transforms" them) and can overcome a G1 cell-cycl arrest induced by p107, a member of the pRb tumour-suppressor family (Adams and Kaelin, 1995). The minimum "transforming" and p107 inhibiting region of Mdm2 corresponds to its p53 binding domain. p53 inhibits transformation by Mdm2, apparently without requiring transcription. p53 can be considered to be a suppressor of Mdm2, a positive effector of the cell cycle. Mdm2 over-expression in tumours is reminiscent of p53 mutations with gain of function, in that Mdm2 both transforms cells and inhibits p53 activity.
p53肿瘤抑制蛋白通过对参与细胞周期调控、DNA复制、修复及凋亡的基因（如p21、GADD45、bax和mdm2）进行转录调控，来响应基因毒性应激，从而保护基因组（考克斯和莱恩，1995年）。经典观点认为，Mdm2是p53的抑制剂，它形成一个自我调节环（莫曼德等人，1992年；奥利纳等人，1993年；吴等人，1993年；陈等人，1994年；陈和莱文，1995年）。它能使含有野生型p53的细胞永生化，并与Ras共同使其发生转化（芬利，1993年）。我们发现，在没有p53的情况下，Mdm2赋予细胞生长优势（即“转化”它们），并且能够克服由pRb肿瘤抑制家族成员p107诱导的G1期细胞周期阻滞（亚当斯和凯林，1995年）。Mdm2的最小“转化”和抑制p107的区域对应于其p53结合结构域。p53抑制Mdm2介导的转化，显然无需转录。p53可被视为Mdm2的抑制剂，而Mdm2是细胞周期的一个正向效应因子。肿瘤中Mdm2的过表达让人联想到具有功能获得性的p53突变，因为Mdm2既能转化细胞，又能抑制p53活性。
