Sherif Zaki A
Department of Biochemistry and Molecular Biology, Howard University College of Medicine, Howard University, Washington, DC 20059, USA.
Genet Res Int. 2015;2015:789201. doi: 10.1155/2015/789201. Epub 2015 Mar 18.
Wild-type p53 is well known to induce cell cycle arrest and apoptosis to block aberrant cell growth. However, p53's unique role in apoptosis and cell proliferation in Li-Fraumeni Syndrome (LFS) has not been well elucidated. The aim of this study is to characterize the activity of wild-type p53 protein in LFS family dominated by a germline negative mutant p53. As expected, etoposide-treated wild-type p53-containing cell lines, LFS 2852 and control Jurkat, showed a greater rate of caspase- and annexin V-induced apoptotic cell death compared to the p53-mutant LFS 2673 cell line although mitochondrial and nuclear assays could not detect apoptosis in these organelles. The most intriguing part of the observation was the abnormal proliferation rate of the wild-type p53-containing cell line, which grew twice as fast as 2673 and Jurkat cells. This is important because apoptosis inducers acting through the mitochondrial death pathway are emerging as promising drugs against tumors where the role of p53 is not only to target gene regulation but also to block cell proliferation. This study casts a long shadow on the possible dysregulation of p53 mediators that enable cell proliferation. The deregulation of proliferation pathways represents an important anticancer therapeutic strategy for patients with the LFS phenotype.
众所周知，野生型p53可诱导细胞周期停滞和凋亡，以阻止异常细胞生长。然而，p53在李-弗劳梅尼综合征（LFS）的凋亡和细胞增殖中的独特作用尚未得到充分阐明。本研究的目的是表征在由种系阴性突变型p53主导的LFS家族中野生型p53蛋白的活性。正如预期的那样，与p53突变的LFS 2673细胞系相比，经依托泊苷处理的含有野生型p53的细胞系LFS 2852和对照Jurkat细胞显示出更高的半胱天冬酶和膜联蛋白V诱导的凋亡细胞死亡率，尽管线粒体和细胞核检测未在这些细胞器中检测到凋亡。观察中最引人关注的部分是含有野生型p53的细胞系的异常增殖率，其生长速度是2673和Jurkat细胞的两倍。这一点很重要，因为通过线粒体死亡途径起作用的凋亡诱导剂正在成为对抗肿瘤的有前景的药物，在这些肿瘤中，p53的作用不仅是靶向基因调控，还包括阻止细胞增殖。这项研究对可能导致细胞增殖的p53介质失调投下了长长的阴影。增殖途径的失调代表了针对LFS表型患者的重要抗癌治疗策略。
