Zhang Jianmin, Pickering Curtis R, Holst Charles R, Gauthier Mona L, Tlsty Thea D
Department of Pathology and UCSF Comprehensive Cancer Center, University of California San Francisco, California 94143, USA.
Cancer Res. 2006 Nov 1;66(21):10325-31. doi: 10.1158/0008-5472.CAN-06-1594.
p16(INK4a) (p16) and p53 are tumor suppressor genes that are inactivated during carcinogenesis in many tumors. Here we show that p16 gene activity inversely modulates p53 status and function in primary human mammary epithelial cells. Reduced levels of p16 protein stabilize p53 protein through inhibition of proteolytic degradation, and this increase in p53 protein levels enhances the cellular response to radiation, represses proliferation, and transcriptionally activates downstream targets. Stabilization of p53 is mediated through the retinoblastoma/E2F/p14(ARF)/murine double minute-2 pathway. However, we have observed that p16 does not modulate p53 in fibroblasts, indicating a possible cell type-specific regulation of this pathway.
p16（INK4a）（p16）和p53是肿瘤抑制基因，在许多肿瘤的致癌过程中会失活。在此我们表明，p16基因活性在原代人乳腺上皮细胞中反向调节p53的状态和功能。p16蛋白水平降低通过抑制蛋白水解降解来稳定p53蛋白，而p53蛋白水平的这种增加增强了细胞对辐射的反应，抑制了增殖，并转录激活下游靶点。p53的稳定是通过视网膜母细胞瘤/E2F/p14（ARF）/小鼠双微体2途径介导的。然而，我们观察到p16在成纤维细胞中不调节p53，这表明该途径可能存在细胞类型特异性调节。
