Restoring function

McCarthy, Nicola

doi:10.1038/nrc3543

In Brief
Published: 24 May 2013

Tumour suppressors

Restoring function

Nicola McCarthy

Nature Reviews Cancer volume 13, page 379 (2013)Cite this article

880 Accesses
Metrics details

Subjects

Access through your institution

Buy or subscribe

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.

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

Purchase on SpringerLink
Instant access to full article PDF

Buy now

Prices may be subject to local taxes which are calculated during checkout

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)
Article CAS Google Scholar

Download references

Authors