Calico Life Sciences LLC, South San Francisco, CA, USA.
Oncology R&D Group, Pfizer Worldwide Research and Development, San Diego, CA, USA.
Sci Rep. 2020 Apr 24;10(1):6966. doi: 10.1038/s41598-020-64009-0.
The naked mole-rat is a subterranean rodent, approximately the size of a mouse, renowned for its exceptional longevity (>30 years) and remarkable resistance to cancer. To explore putative mechanisms underlying the cancer resistance of the naked mole-rat, we investigated the regulation and function of the most commonly mutated tumor suppressor, TP53, in the naked mole-rat. We found that the p53 protein in naked mole-rat embryonic fibroblasts (NEFs) exhibits a half-life more than ten times in excess of the protein's characterized half-life in mouse and human embryonic fibroblasts. We determined that the long half-life of the naked mole-rat p53 protein reflects protein-extrinsic regulation. Relative to mouse and human p53, a larger proportion of naked mole-rat p53 protein is constitutively localized in the nucleus prior to DNA damage. Nevertheless, DNA damage is sufficient to induce activation of canonical p53 target genes in NEFs. Despite the uniquely long half-life and unprecedented basal nuclear localization of p53 in NEFs, naked mole-rat p53 retains its canonical tumor suppressive activity. Together, these findings suggest that the unique stabilization and regulation of the p53 protein may contribute to the naked mole-rat's remarkable resistance to cancer.
裸鼹鼠是一种地下啮齿动物，大小近似于老鼠，以极长的寿命（>30 年）和显著的抗癌能力而闻名。为了探究裸鼹鼠抗癌能力的潜在机制，我们研究了最常见的突变型肿瘤抑制因子 TP53 在裸鼹鼠中的调控和功能。我们发现裸鼹鼠胚胎成纤维细胞（NEFs）中的 p53 蛋白半衰期超过小鼠和人胚胎成纤维细胞中 p53 蛋白特征半衰期的十倍以上。我们确定裸鼹鼠 p53 蛋白的长半衰期反映了蛋白外在的调控。与小鼠和人类的 p53 相比，裸鼹鼠 p53 蛋白中有更大比例在 DNA 损伤之前就持续定位于细胞核中。然而，DNA 损伤足以诱导 NEFs 中经典 p53 靶基因的激活。尽管裸鼹鼠 p53 的半衰期独特地长，且在 NEFs 中有前所未有的基础核定位，但它仍然保留着其经典的肿瘤抑制活性。这些发现表明，p53 蛋白的独特稳定性和调控可能有助于裸鼹鼠对癌症的显著抗性。
