p16INK4a induces an age-dependent decline in islet regenerative potential
p16INK4a induces an age-dependent decline in islet regenerative potential
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DOI：
10.1038/nature05092
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发表时间：
2006-09-28
期刊：
影响因子：
64.8
通讯作者：
Sharpless, Norman E.
中科院分区：
文献类型：
--
作者：
Krishnamurthy, Janakiraman;Ramsey, Matthew R.;Sharpless, Norman E.
p16（INK 4a）肿瘤抑制因子随着年龄的增长在许多组织中积累（1-3）。p16（INK 4a）是衰老效应子（4，5）和增殖激酶Cdk 4的有效抑制剂（参考文献6），Cdk 4对成年哺乳动物的胰腺β细胞增殖至关重要（7，8）。在这里，我们表明，p16（INK 4a）抑制胰岛增殖和再生的年龄依赖性的方式。与胰腺外分泌相比，纯化的胰岛中p16（INK 4a）转录物的表达更丰富，并且胰岛特异性表达p16（INK 4a），而不是其他细胞周期蛋白依赖性激酶抑制剂，随着年龄的增长显着增加。为了确定p16（INK 4a）积累对胰岛功能的生理意义，我们评估了p16（INK 4a）缺陷和过度表达随年龄增长的影响，以及暴露于特定β细胞毒素后的再生反应。过度表达p16（INK 4a）到一定程度的转基因小鼠随着年龄的增长表现出胰岛增殖减少。类似地，胰岛增殖在年轻小鼠中不受p16（INK 4a）缺陷的影响，但在p16（INK 4a）缺陷的老年小鼠中相对增加。毒素介导的β细胞消融后的存活率（需要胰岛增殖）随着年龄的增长而下降;然而，缺乏p16（INK 4a）的小鼠在β细胞消融后表现出增强的胰岛增殖和存活率。这些遗传数据支持这样的观点，即年龄诱导的p16（INK 4a）表达增加限制了β细胞随着衰老的再生能力。
The p16(INK4a) tumour suppressor accumulates in many tissues as a function of advancing age(1-3). p16(INK4a) is an effector of senescence(4,5) and a potent inhibitor of the proliferative kinase Cdk4 (ref. 6), which is essential for pancreatic beta-cell proliferation in adult mammals(7,8). Here we show that p16(INK4a) constrains islet proliferation and regeneration in an age-dependent manner. Expression of the p16(INK4a) transcript is enriched in purified islets compared with the exocrine pancreas, and islet-specific expression of p16(INK4a), but not other cyclin-dependent kinase inhibitors, increases markedly with ageing. To determine the physiological significance of p16(INK4a) accumulation on islet function, we assessed the impact of p16(INK4a) deficiency and overexpression with increasing age and in the regenerative response after exposure to a specific beta-cell toxin. Transgenic mice that overexpress p16(INK4a) to a degree seen with ageing demonstrated decreased islet proliferation. Similarly, islet proliferation was unaffected by p16(INK4a) 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 p16(INK4a) demonstrated enhanced islet proliferation and survival after beta-cell ablation. These genetic data support the view that an age-induced increase of p16(INK4a) expression limits the regenerative capacity of beta-cells with ageing.