Every year, nearly 90% of advanced melanomas have lost a working copy of the p16 gene, and families who inherit a defective version are highly susceptible to this skin cancer. This project tackles a fundamental gap in knowledge: how the p16 protein is switched on when cells detect DNA damage or excessive division, triggering a permanent halt to growth called senescence. While the related p53 protein’s activation pathway is well understood, the chain of events that activates p16 remains largely unknown. The researchers will map how DNA damage signalling modifies p16 by adding or removing small molecules like phosphate and ubiquitin, and test whether these modifications are broken in melanoma cells that have a normal p16 gene but produce no detectable protein. If successful, the work could improve diagnostic antibodies used to distinguish cancers from benign growths, and might eventually point to ways to temporarily suppress senescence in conditions like slow-healing skin ulcers. This is fundamental science—understanding a core tumour suppressor’s regulation—but the same protein that fails in most advanced melanomas is also central to ageing, giving the results wide potential relevance.
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Our bodies have some impressive mechanisms to block cancer development, which rarely fail over our lifetimes. A major such mechanism is triggered when cells detect that they have divided too many times, or they have seriously damaged DNA. Then they can permanently block their own division (although without dying), which is called cell senescence. Cell senescence is also important in ageing and age-related diseases. It has become intensively studied since 2000. It is controlled mainly through two proteins called p16 and p53. These are the two proteins that most frequently become defective or lost in human cancers. Some families inherit a defective copy of p16’s gene, which makes them very susceptible to melanoma, the most dangerous skin cancer and the fifth commonest cancer in the UK. This gene is also defective or lost in nearly 90% of all advanced melanomas. The cellular/molecular mechanism for senescence has two branches, controlled respectively by p16 and p53. The central trigger for both branches appears to be DNA damage signalling (DDS), a cascade of signalling molecules generated by cells with DNA damage, and by cells that divided many times (these have DDS at the ends of chromosomes, called telomeres). Much is known about how p53 is activated by DDS, but remarkably little about p16. Cells often regulate proteins by adding small molecules to them. For example p53 becomes more stable and active by adding phosphates, or less stable by adding the molecule ubiquitin. DDS promotes phosphate addition and inhibits ubiquitin addition, greatly stabilizing p53. Such protein modifications were not thought to happen to p16 until 2003, since when a few groups have reported that human p16 can also have small molecules added, including phosphate, methyl groups and ubiquitin. The additions are at specific sites (amino acids) on the protein. Interestingly these sites are conserved in some primates but not other mammals. These modifications provide exciting yet barely-explored possibilities for rapid regulation of human p16, including by DDS. Our pilot data indicate strong effects of DDS on p16 abundance. Blocking DDS leads to loss or attenuation of p16 protein in HeLa cervical cancer cells and senescent normal human pigment cells (melanocytes, the cell from which melanomas originate). Here we aim to unravel the chain of events by which DDS activates p16 in human cells, identify intermediate signalling molecules and determine the extent to which phosphate and ubiquitin addition are involved. The mechanisms found will be tested for defects in cultured human melanoma cell lines known to contain a normal gene and messenger RNA for p16, but no detectable protein. The study will also show whether antibodies against p16 (used to diagnose some cancers versus harmless benign growths) can effectively detect modified versions, e.g. with phosphate. The results may have wide implications for both cancer and ageing in humans. For example they may allow us to generate better diagnostic antibodies that react with all forms of p16, or specifically with active forms. They may allow temporary suppression of cell senescence in contexts such as defective skin healing (senile ulcers). They may illuminate additional mechanisms in cancer development through genetic defects in p16 activation, and permit development of therapies that restore the activation mechanism. Potential beneficiaries are thus cancer patients and at least some of those with age-related disorders.
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