Nikiforov M A, Kwek S S, Mehta R, Artwohl J E, Lowe S W, Gupta T D, Deichman G I, Gudkov A V
Department of Genetics, University of Illinois at Chicago, 60607-7170, USA.
Oncogene. 1997 Dec 18;15(25):3007-12. doi: 10.1038/sj.onc.1201723.
Mutations in the p53 tumor suppressor gene are frequently associated with the metastatic stage of tumor progression. Inactivation of p53 was shown to promote metastasis under experimental conditions. To determine the p53 functions that are involved in the control of tumor metastasis, we compared properties of three types of transformed mouse fibroblasts: with intact p53, with p53-mediated apoptosis suppressed by bcl-2 and with p53 inactivated by dominant negative mutants. Although expression of bcl-2 blocked apoptosis in detached cells and increased tumor cell survival in the blood circulation, it was insufficient to affect the ability of p53 to cause cell cycle arrest in detached cells and suppress experimental metastasis. For the suppression of metastasis complete inactivation of p53 was required. We conclude that the apoptotic function of p53 is dispensable for the p53-dependent suppression of experimental metastasis that is presumably achieved by controlling anchorage dependence. These data provide a possible explanation to dramatic differences in values of bcl-2 and mutant p53 as prognostic markers in human cancer.
p53肿瘤抑制基因的突变常常与肿瘤进展的转移阶段相关。在实验条件下，p53的失活被证明可促进转移。为了确定参与控制肿瘤转移的p53功能，我们比较了三种类型的转化小鼠成纤维细胞的特性：p53完整的细胞、bcl-2抑制p53介导的凋亡的细胞以及显性负性突变体使p53失活的细胞。虽然bcl-2的表达阻断了脱离细胞中的凋亡并增加了肿瘤细胞在血液循环中的存活，但它不足以影响p53在脱离细胞中导致细胞周期停滞和抑制实验性转移的能力。为了抑制转移，需要p53完全失活。我们得出结论，p5可能通过控制锚定依赖性来实现的对实验性转移的抑制中，p53的凋亡功能是可有可无的。这些数据为bcl-2和突变型p53作为人类癌症预后标志物的值存在巨大差异提供了一种可能的解释。
