Frazier M W, He X, Wang J, Gu Z, Cleveland J L, Zambetti G P
Department of Biochemistry, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Mol Cell Biol. 1998 Jul;18(7):3735-43. doi: 10.1128/MCB.18.7.3735.
Mutation of the p53 tumor suppressor gene is the most common genetic alteration in human cancer, and tumors that express mutant p53 may be more aggressive and have a worse prognosis than p53-null cancers. Mutant p53 enhances tumorigenicity in the absence of a transdominant negative mechanism, and this tumor-promoting activity correlates with its ability to transactivate reporter genes in transient transfection assays. However, the mechanism by which mutant p53 functions in transactivation and its endogenous cellular targets that promote tumorigenicity are unknown. Here we report that (i) mutant p53 can regulate the expression of the endogenous c-myc gene and is a potent activator of the c-myc promoter; (ii) the region of mutant p53 responsiveness in the c-myc gene has been mapped to the 3' end of exon 1; (iii) the mutant p53 response region is position and orientation dependent and therefore does not function as an enhancer; and (iv) transactivation by mutant p53 requires the C terminus, which is not essential for wild-type p53 transactivation. These data suggest that it may be possible to selectively inhibit mutant p53 gain of function and consequently reduce the tumorigenic potential of cancer cells. A possible mechanism for transactivation of the c-myc gene by mutant p53 is proposed.
p53肿瘤抑制基因的突变是人类癌症中最常见的基因改变，表达突变型p53的肿瘤可能比p53缺失的癌症更具侵袭性，预后更差。在没有反式显性负性机制的情况下，突变型p53增强了致瘤性，并且这种肿瘤促进活性与其在瞬时转染试验中转录激活报告基因的能力相关。然而，突变型p53在反式激活中发挥作用的机制及其促进致瘤性的内源性细胞靶点尚不清楚。在此我们报告：（i）突变型p53可调节内源性c-myc基因的表达，并且是c-myc启动子的强效激活剂；（ii）c-myc基因中突变型p53反应性区域已定位到外显子1的3'端；（iii）突变型p53反应区域依赖于位置和方向，因此不作为增强子发挥作用；以及（iv）突变型p53的反式激活需要C末端，而这对于野生型p53的反式激活并非必需。这些数据表明，有可能选择性地抑制突变型p53的功能获得，从而降低癌细胞的致瘤潜力。本文提出了突变型p53反式激活c-myc基因的一种可能机制。
