Sigal A, Rotter V
Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
Cancer Res. 2000 Dec 15;60(24):6788-93.
The p53 guardian of the genome is inactivated in the majority of cancers, mostly through missense mutations that cause single residue changes in the DNA binding core domain of the protein. Not only do such mutations result in the abrogation of wild-type p53 activity, but the expressed p53 mutant proteins also tend to gain oncogenic functions, such as interference with wild-type p53-independent apoptosis. Because p53 mutants are highly expressed in cancer cells and not in normal cells, their reactivation to wild-type p53 function may eliminate the cancer by apoptosis or another p53-dependent mechanism. Several studies that embarked on this quest for reactivation have succeeded in restoring wildtype p53 activity to several p53 mutants. However, mutants with more extensive structural changes in the DNA binding core domain may be refractory to reactivation to the wild-type p53 phenotype. Therefore, understanding the structure and functions of oncogenic p53 mutants may lead to more potent reactivation modalities or to the ability to eliminate mutant p53 gain of function.
基因组守护者p53在大多数癌症中失活，主要是通过错义突变导致该蛋白DNA结合核心结构域中的单个残基发生变化。这类突变不仅会导致野生型p53活性丧失，而且所表达的p53突变蛋白还往往会获得致癌功能，比如干扰不依赖野生型p53的细胞凋亡。由于p53突变体在癌细胞中高表达而在正常细胞中不表达，将它们重新激活为野生型p53功能可能会通过细胞凋亡或其他p53依赖机制消除癌症。几项致力于此重新激活探索的研究已成功将几种p53突变体恢复为野生型p53活性。然而，在DNA结合核心结构域中具有更广泛结构变化的突变体可能难以重新激活为野生型p53表型。因此，了解致癌性p53突变体的结构和功能可能会带来更有效的重新激活方式，或具备消除突变p53功能获得的能力。
