A high proportion of malignant melanomas express wild-type p53 that is often inactive. Xin Lu and colleagues have found that most malignant melanoma cell lines with wild-type p53 have high levels of phosphorylated iASPP in the nucleus. iASPP interacts with p53 and inhibits apoptosis, and these authors found that iASPP is phosphorylated by cyclin B1–cyclin-dependent kinase 1 (CDK1). This prevents dimerization of iASPP and enables the monomeric phosphorylated form of iASPP to accumulate in the nucleus and to interact with p53. Previous studies have shown that wild-type p53 activity can be increased in cancer cells through the use of inhibitors of MDM2, a ubiquitin ligase that binds and ubiquitylates p53, which can result in its degradation. Inhibition of iASPP phosphorylation and MDM2 activity using small-molecule inhibitors resulted in apoptosis and growth suppression of wild-type p53 melanoma cell lines. Moreover, this approach combined with the BRAF inhibitor vemurafenib substantially reduced the growth of human melanoma xenografts with wild-type p53 and a BRAF-V600E mutation.
ORIGINAL RESEARCH PAPER
Lu, M. et al. Restoring p53 function in human melanoma cells by inhibiting MDM2 and cyclin B1/CDK1-phosphorylated nuclear iASPP. Cancer Cell 25 Apr 2013 (doi:10.1016/j.ccr.2013.03.013)
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McCarthy, N. Restoring function. Nat Rev Cancer 13, 379 (2013). https://doi.org/10.1038/nrc3543
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DOI: https://doi.org/10.1038/nrc3543