Highlighted Paper: Contrasting behavior of the p18INK4c and p16INK4a tumor suppressors in both replicative and oncogene-induced senescence

The Molecular Oncology Lab headed by Gordon Peters published the following article in Cancer Research last month.

Gagrica S, Brookes S, Anderton E, Rowe J, Peters G. Contrasting behavior of the p18^INK4c and p16^INK4a tumor suppressors in both replicative and oncogene-induced senescence. Cancer Res. (Abstract)

The p16^INK4a gene is frequently deleted or inactivated in human cancer. The likely reason is that p16^INK4a is responsible for stopping the proliferation of cells that have acquired a cancer causing mutation, in a process known as “cellular senescence”. Senescence sets limits on the number of times a cell can divide but can also be caused by DNA damage or other forms of stress. For cancer to progress, the tumour cells have to escape from senescence. 

Recently, it was reported that the gene encoding p18^INK4c, a close relative of p16^INK4a, is also deleted in human brain tumours and, in some cases, this happens in cells that have already lost p16^INK4a.  It was proposed that p18^INK4c acts as a backup for p16^INK4a but our findings suggest a different explanation.  In cells undergoing senescence, for whatever reason, there is a dramatic decline in the levels of p18^INK4c which effectively mirrors the characteristic accumulation of p16^INK4a (see Figure). The loss of p18^INK4c at senescence can be partly explained by reduced levels of E2F1, a protein that controls the expression of the p18^INK4c gene.  However, we found no evidence that p18^INK4c is activated by the loss of p16^INK4a as previously suggested; rather, the absence of p16^INK4a delays senescence and therefore the point at which p18INK4c is turned off.  The contrasting behaviour of the two INK4 proteins implies that p18^INK4c is not simply substituting for p16^INK4a and is regulated in a completely different way. We speculate that while the tumour suppressive properties of p16^INK4a relate to senescence, those of p18^INK4c could reflect its role in differentiation.