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Restoring p53 function in human melanoma cells by inhibiting MDM2 and cyclin B1/CDK1-phosphorylated nuclear iASPP.

Lu, M; Breyssens, H; Salter, V; Zhong, S; Hu, Y; Baer, C; Ratnayaka, I; ... Lu, X; + view all (2013) Restoring p53 function in human melanoma cells by inhibiting MDM2 and cyclin B1/CDK1-phosphorylated nuclear iASPP. Cancer Cell , 23 (5) pp. 618-633. 10.1016/j.ccr.2013.03.013.

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Abstract

Nearly 90% of human melanomas contain inactivated wild-type p53, the underlying mechanisms for which are not fully understood. Here, we identify that cyclin B1/CDK1-phosphorylates iASPP, which leads to the inhibition of iASPP dimerization, promotion of iASPP monomer nuclear entry, and exposure of its p53 binding sites, leading to increased p53 inhibition. Nuclear iASPP is enriched in melanoma metastasis and associates with poor patient survival. Most wild-type p53-expressing melanoma cell lines coexpress high levels of phosphorylated nuclear iASPP, MDM2, and cyclin B1. Inhibition of MDM2 and iASPP phosphorylation with small molecules induced p53-dependent apoptosis and growth suppression. Concurrent p53 reactivation and BRAFV600E inhibition achieved additive suppression in vivo, presenting an alternative for melanoma therapy.

Type: Article
Title: Restoring p53 function in human melanoma cells by inhibiting MDM2 and cyclin B1/CDK1-phosphorylated nuclear iASPP.
Location: United States
DOI: 10.1016/j.ccr.2013.03.013
Keywords: Active Transport, Cell Nucleus, Animals, Antineoplastic Agents, Apoptosis, CDC2 Protein Kinase, Cell Line, Tumor, Cell Nucleus, Cell Proliferation, Cyclin B1, Dimerization, Humans, Imidazoles, Indoles, Intracellular Signaling Peptides and Proteins, M Phase Cell Cycle Checkpoints, Melanoma, Mice, Neoplasm Metastasis, Nocodazole, Phosphorylation, Piperazines, Proto-Oncogene Proteins c-mdm2, Repressor Proteins, Sulfonamides, Triazoles, Tumor Suppressor Protein p53, Vemurafenib, Xenograft Model Antitumor Assays
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Cell and Developmental Biology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Oncology
URI: http://discovery.ucl.ac.uk/id/eprint/1484744
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