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The Lu lab reveals that the previously characterised oncogene, iASPP, acts as a tumour suppressor in mutant RAS- and inflammation-driven skin cancers.

There is a tightly regulated balance between cell growth and death in healthy tissue. The loss of this balance is essentially what initiates cancer.

At a molecular level, that imbalance stems from a cell’s acquisition of both activating mutations that promote its proliferation and the loss of inhibitory factors that suppress unregulated growth. In many cases, this imbalance is caused by activating mutations in the RAS signalling pathway and mutations of the p53 tumor suppressor gene, respectively. Cancers driven by RAS signalling that are also associated with inflammation can, however, bypass the need for p53 pathway dysfunction. How these cancers are able to initiate when the p53 tumour suppressor is not mutated was not entirely clear.

To find out, Ludwig Oxford’s Dr Khatoun Al Moussawi, Dr Kathryn Chung, Dr Thomas Carroll and Dr Artem Smirnov in Professor Xin Lu’s lab, Dr Christian Osterburg at Goethe University in Germany and colleagues elsewhere explored carcinogenesis in a well-established mouse model of mutant RAS- and inflammation-driven skin cancer. Their findings, described in Cell Reports, reveal that iASPP, which typically promotes tumour growth by inhibiting p53, unexpectedly suppresses cancer initiation in this context.

This, they report, is because iASPP has a p53-independent role in skin homeostasis, where it regulates the expression of a subset of genes targeted by the p63 and AP1 transcription factors, including several involved in inflammation and cellular differentiation. iASPP coordinates the crosstalk between the JNK signalling pathway and p53/p63 to maintain skin homeostasis. This newly uncovered role of iASPP may help explain how iASPP can both drive and suppress cancer, depending on its context.

Since dysregulation of the JNK, iASPP, AP1 and p63 pathways cause disease in animals and humans, the discovery of previously unrecognised interactions between these pathways is also of biological significance. 

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