Krishnamurthy Janakiraman, Ramsey Matthew R, Ligon Keith L, Torrice Chad, Koh Angela, Bonner-Weir Susan, Sharpless Norman E
Department of Medicine, The Lineberger Comprehensive Cancer Center, The University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599, USA.
Nature. 2006 Sep 28;443(7110):453-7. doi: 10.1038/nature05092. Epub 2006 Sep 6.
The p16INK4a tumour suppressor accumulates in many tissues as a function of advancing age. p16INK4a is an effector of senescence and a potent inhibitor of the proliferative kinase Cdk4 (ref. 6), which is essential for pancreatic beta-cell proliferation in adult mammals. Here we show that p16INK4a constrains islet proliferation and regeneration in an age-dependent manner. Expression of the p16INK4a transcript is enriched in purified islets compared with the exocrine pancreas, and islet-specific expression of p16INK4a, but not other cyclin-dependent kinase inhibitors, increases markedly with ageing. To determine the physiological significance of p16INK4a accumulation on islet function, we assessed the impact of p16INK4a deficiency and overexpression with increasing age and in the regenerative response after exposure to a specific beta-cell toxin. Transgenic mice that overexpress p16INK4a to a degree seen with ageing demonstrated decreased islet proliferation. Similarly, islet proliferation was unaffected by p16INK4a deficiency in young mice, but was relatively increased in p16(INK4a)-deficient old mice. Survival after toxin-mediated ablation of beta-cells, which requires islet proliferation, declined with advancing age; however, mice lacking p16INK4a demonstrated enhanced islet proliferation and survival after beta-cell ablation. These genetic data support the view that an age-induced increase of p16INK4a expression limits the regenerative capacity of beta-cells with ageing.
随着年龄的增长，p16INK4a肿瘤抑制因子在许多组织中积累。p16INK4a是衰老的效应因子，也是增殖激酶Cdk4的有效抑制剂（参考文献6），而Cdk4对成年哺乳动物胰腺β细胞的增殖至关重要。在此，我们表明p16INK4a以年龄依赖性方式限制胰岛增殖和再生。与外分泌胰腺相比，p16INK4a转录本在纯化的胰岛中表达丰富，且p16INK4a而非其他细胞周期蛋白依赖性激酶抑制剂的胰岛特异性表达随衰老显著增加。为了确定p16INK4a积累对胰岛功能的生理意义，我们评估了随着年龄增长以及在暴露于特定β细胞毒素后的再生反应中，p16INK4a缺乏和过表达的影响。过度表达p16INK4a至衰老时所见程度的转基因小鼠表现出胰岛增殖减少。同样，年轻小鼠中p16INK4a缺乏对胰岛增殖无影响，但在p16(INK4a)缺乏的老年小鼠中胰岛增殖相对增加。毒素介导的β细胞消融后的存活需要胰岛增殖，其随年龄增长而下降；然而，缺乏p16INK4a的小鼠在β细胞消融后表现出增强的胰岛增殖和存活。这些遗传学数据支持这样一种观点，即随着年龄增长，p16INK4a表达的增加会限制β细胞的再生能力。
