Abarzúa P, LoSardo J E, Gubler M L, Spathis R, Lu Y A, Felix A, Neri A
Roche Research Center, Hoffmann-LaRoche Inc, Nutley, New Jersey 07110, USA.
Oncogene. 1996 Dec 5;13(11):2477-82.
The p53 tumor suppressor gene product is a sequence-specific transcription activator frequently mutated in a variety of human malignancies. Typically, tumor-derived p53 missense mutants are defective in DNA binding and this is likely to result in a failure to active p53-regulated genes. Hence, restoring function to mutant p53 represents an attractive target to develop a novel cancer chemotherapeutic agent. We now show that a small chemically modified peptide derived from p53 restores sequence-specific DNA binding to a subset of p53 mutants. Moreover, when microinjected into human colon carcinoma cells this peptide restores the transcription activation function to endogenous mutant p53 protein. This is the first example showing that a small peptide molecule can reverse the effect of several inactivating missense mutations and restore protein function.
p53肿瘤抑制基因产物是一种序列特异性转录激活因子，在多种人类恶性肿瘤中经常发生突变。通常，肿瘤来源的p53错义突变体在DNA结合方面存在缺陷，这可能导致无法激活p53调控的基因。因此，恢复突变型p53的功能是开发新型癌症化疗药物的一个有吸引力的靶点。我们现在表明，一种源自p53的化学修饰小肽可恢复对一部分p53突变体的序列特异性DNA结合。此外，当将这种肽显微注射到人类结肠癌细胞中时，它可恢复内源性突变型p53蛋白的转录激活功能。这是第一个表明小肽分子可以逆转几种失活错义突变的作用并恢复蛋白质功能的例子。
