Yesterday we learned how a tumor suppressor gene called p16INK4a limits the self-renewal potential of hematopoietic stem cells, and discussed the way in which this reflects a tradeoff between tissue replenishment and cancer prevention. Today I want to draw your attention to a related paper by Krishnamurthy et al., who show that p16INK4a is similarly constraining the ability of pancreatic ß cells to proliferate and self-renew:

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, 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 p16INK4a-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.

The diabetes model here, in which a toxin destroys the ß cells, is apropos of type II “adult onset” diabetes, in which insulin resistance forces the ß cells to synthesize and secrete more and more insulin until eventually endoplasmic reticulum folding stress and proteotoxicity destroys the cells altogether. p16INK4a limits the ability of islet cells to survive, proliferate, and reconstitute the organ’s ability to serve one of its vital functions.

As with the stem cell story yesterday, we note the temptation would be to try to design drugs against p16INK4a as a means of preventing adult-onset diabetes in humans. Again, sadly, we must also note that p16INK4a null mice are cancer-prone, so such an approach might end up trading an unfortunate but manageable condition for one of the most terrifying cancer diagnoses on the books.

There is the possibility that a treatment regimen might suppress p16INK4a for acute periods, in order to allow ß cell regrowth up to some functional threshold, after which p16INK4a activity would return to normal levels and resume its cancer-prevention function. Such an application, however, is years away: Because of the potential cancer tradeoff, more detailed studies will need to be performed in animal conditional mutants (where the gene can be turned on and off at different times) in order to assess the risks.

Even more challenging, we still need a way to safely target gene knockdowns to specific populations of cells in intact human bodies. While there’s promising progress reported almost every week, the job is still far from finished.