Selivanova G, Wiman K G
Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
Oncogene. 2007 Apr 2;26(15):2243-54. doi: 10.1038/sj.onc.1210295.
The p53 tumor suppressor gene is the most frequently mutated gene in cancer. Most p53 mutations are missense point mutations that cluster in the DNA-binding core domain. This results in distortion of core domain folding and disruption of DNA binding and transcriptional transactivation of p53 target genes. Structural studies have demonstrated that mutant p53 core domain unfolding is not irreversible. Mutant p53 is expressed at high levels in many tumors. Therefore, mutant p53 is a promising target for novel cancer therapy. Mutant p53 reactivation will restore p53-dependent apoptosis, resulting in efficient removal of tumor cells. A number of strategies for targeting mutant p53 have been designed, including peptides and small molecules that restore the active conformation and DNA binding to mutant p53 and induce p53-dependent suppression of tumor cell growth in vitro and in vivo. This opens possibilities for the clinical application of mutant p53 reactivation in the treatment of cancer.
p53肿瘤抑制基因是癌症中最常发生突变的基因。大多数p53突变是错义点突变，集中在DNA结合核心结构域。这导致核心结构域折叠变形，破坏DNA结合以及p53靶基因的转录反式激活。结构研究表明，突变型p53核心结构域的解折叠并非不可逆。突变型p53在许多肿瘤中高表达。因此，突变型p53是新型癌症治疗的一个有前景的靶点。突变型p53的重新激活将恢复p53依赖的细胞凋亡，从而有效清除肿瘤细胞。已经设计了多种靶向突变型p53的策略，包括能够恢复突变型p53的活性构象和DNA结合能力并在体外和体内诱导p53依赖的肿瘤细胞生长抑制的肽和小分子。这为突变型p53重新激活在癌症治疗中的临床应用开辟了可能性。
