1. Departments of Medicine and Genetics, The Lineberger Comprehensive Cancer Center, The University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599, USA
2. Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA
3. Joslin Diabetes Center and Harvard Medical School, Boston, Massachusetts 02115, USA

Correspondence to: Norman E. Sharpless¹ Correspondence and requests for materials should be addressed to N.E.S. (Email: NES@med.unc.edu).

Abstract

The p16^INK4a tumour suppressor accumulates in many tissues as a function of advancing age^{1, 2, 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 -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 -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 -cells, which requires islet proliferation, declined with advancing age; however, mice lacking p16^INK4a demonstrated enhanced islet proliferation and survival after -cell ablation. These genetic data support the view that an age-induced increase of p16^INK4a expression limits the regenerative capacity of -cells with ageing.

1. Departments of Medicine and Genetics, The Lineberger Comprehensive Cancer Center, The University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599, USA
2. Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA
3. Joslin Diabetes Center and Harvard Medical School, Boston, Massachusetts 02115, USA

Correspondence to: Norman E. Sharpless¹ Correspondence and requests for materials should be addressed to N.E.S. (Email: NES@med.unc.edu).

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