Zalcenstein Amir, Stambolsky Perry, Weisz Lilach, Müller Martina, Wallach David, Goncharov Tanya M, Krammer Peter H, Rotter Varda, Oren Moshe
Department of Molecular Cell Biology, Weizmann Institute of Science, PO Box 26, Rehovot, 76100, Israel.
Oncogene. 2003 Aug 28;22(36):5667-76. doi: 10.1038/sj.onc.1206724.
Tumor-associated mutant forms of p53 can exert an antiapoptotic gain of function activity, which probably confers a selective advantage upon tumor cells harboring such mutations. We report that mutant p53 suppresses the expression of the CD95 (Fas/APO-1) gene, encoding a death receptor implicated in a variety of apoptotic responses. Moderate (40-50%) downregulation of CD95 mRNA and surface protein expression by mutant p53 correlates with partial protection against CD95-dependent cell death. Excess mutant p53 represses the transcriptional activity of the CD95 promoter, with the extent of repression varying among different tumor-associated p53 mutants. Furthermore, mutant p53 protein binds the CD95 promoter in vitro, in a region distinct from the one implicated in tight interactions of the CD95 gene with wild-type p53. Hence, the CD95 promoter is likely to be a direct target for downregulation by mutant p53. This activity of mutant p53 may contribute to its gain of function effects in oncogenesis.
肿瘤相关的p53突变形式可发挥抗凋亡的功能获得性活性，这可能赋予携带此类突变的肿瘤细胞一种选择性优势。我们报告，突变型p53抑制CD95（Fas/APO-1）基因的表达，该基因编码一种参与多种凋亡反应的死亡受体。突变型p53使CD95 mRNA和表面蛋白表达适度下调（40%-50%），这与对CD95依赖性细胞死亡的部分保护相关。过量的突变型p53抑制CD95启动子的转录活性，不同肿瘤相关的p53突变体的抑制程度有所不同。此外，突变型p53蛋白在体外与CD95启动子结合，结合区域与CD95基因和野生型p53紧密相互作用所涉及的区域不同。因此，CD95启动子很可能是突变型p53下调的直接靶点。突变型p53的这种活性可能有助于其在肿瘤发生过程中的功能获得性效应。
