Restoring p53 Function in Human Melanoma Cells by Inhibiting MDM2 and Cyclin B1/CDK1-Phosphorylated Nuclear iASPP

• Published in: Cancer cell Vol. 23; no. 5; pp. 618 - 633
• Main Authors: Lu, Min, Breyssens, Hilde, Salter, Victoria, Zhong, Shan, Hu, Ying, Baer, Caroline, Ratnayaka, Indrika, Sullivan, Alex, Brown, Nicholas R., Endicott, Jane, Knapp, Stefan, Kessler, Benedikt M., Middleton, Mark R., Siebold, Christian, Jones, E. Yvonne, Sviderskaya, Elena V., Cebon, Jonathan, John, Thomas, Caballero, Otavia L., Goding, Colin R., Lu, Xin
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 13.05.2013
• Subjects: Active Transport, Cell Nucleus - drug effects; Animals; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; CDC2 Protein Kinase - genetics; CDC2 Protein Kinase - metabolism; CDC2 Protein Kinase - physiology; Cell Line, Tumor; Cell Nucleus - metabolism; Cell Proliferation - drug effects; Cyclin B1 - genetics; Cyclin B1 - metabolism; Cyclin B1 - physiology; Dimerization; Humans; Imidazoles - pharmacology; Indoles - pharmacology; Intracellular Signaling Peptides and Proteins - analysis; Intracellular Signaling Peptides and Proteins - metabolism; M Phase Cell Cycle Checkpoints; Melanoma - genetics; Melanoma - metabolism; Melanoma - pathology; Mice; Neoplasm Metastasis; Nocodazole - pharmacology; Phosphorylation - drug effects; Piperazines - pharmacology; Proto-Oncogene Proteins c-mdm2 - analysis; Proto-Oncogene Proteins c-mdm2 - metabolism; Repressor Proteins - analysis; Repressor Proteins - metabolism; Sulfonamides - pharmacology; Triazoles - pharmacology; Tumor Suppressor Protein p53 - physiology; Vemurafenib; Xenograft Model Antitumor Assays

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 it...