Aging-associated truncated form of p53 interacts with wild-type p53 and alters p53 stability, localization, and activity

作者：Moore Lynette; Lu Xiongbin; Ghebranious Nader; Tyner Stuart; Donehower Lawrence A^*

来源：Mechanisms of Ageing and Development, 2007, 128(11-12): 717-730.

DOI：10.1016/j.mad.2007.10.011

• p53
• Mdm2
• premature aging
• mouse aging model

Evidence has accumulated that p53, a prototypical tumor suppressor, may also influence aspects of organismal aging. We have previously described a p53 mutant mouse model, the p53+/m mouse, which is cancer resistant yet exhibits reduced longevity and premature aging phenotypes. p53+/m mice express one full length p53 allele and one truncated p53 allele that is translated into a C-terminal fragment of p53 termed the M protein. The augmented cancer resistance and premature aging phenotypes in the p53+/m mice are consistent with a hyperactive p53 state. To determine how the M protein could increase p53 activity, we examined the M protein in various cellular contexts. Here, we show that embryo fibroblasts from p53+/m mice exhibit reduced proliferation and cell cycle progression compared to embryo fibroblasts from p53+/- mice (with equivalent wild-type p53 dosage). The M protein interacts with wild-type p53, increases its stability, and facilitates its nuclear localization in the absence of stress. Despite increasing p53 stability, the M protein does not disrupt p53-Mdm2 interactions and does not prevent p53 ubiquitination. These results suggest molecular mechanisms by which the M protein could influence the aging and cancer resistance phenotypes in the p53+/m Mouse.

• 出版日期2007-12