Somatic Mutations in MAP3K5 Attenuate Its Proapoptotic Function in Melanoma Through Increased Binding to Thioredoxin

Overview

Journal J Invest Dermatol

Publisher Elsevier

Specialty Dermatology

Date 2013 Sep 7

PMID 24008424

Citations 13

Authors

Todd D Prickett

Brad Zerlanko

Jared J Gartner

Stephen C J Parker

Ken Dutton-Regester

Jimmy C Lin

Jamie K Teer

Xiaomu Wei

Jiji Jiang

Nisc Comparative Sequencing Program

Guo Chen

Michael A Davies

Jeffrey E Gershenwald

William Robinson

Steven Robinson

Nicholas K Hayward

Steven A Rosenberg

Elliott H Margulies

Yardena Samuels

Affiliations

Soon will be listed here.

Abstract

Patients with advanced metastatic melanoma have poor prognosis and the genetics underlying its pathogenesis are poorly understood. High-throughput sequencing has allowed comprehensive discovery of somatic mutations in cancer samples. Here, on analysis of our whole-genome and whole-exome sequencing data of 29 melanoma samples, we identified several genes that harbor recurrent nonsynonymous mutations. These included MAP3K5 (mitogen-activated protein kinase kinase kinase-5), which in a prevalence screen of 288 melanomas was found to harbor a R256C substitution in 5 cases. All MAP3K5-mutated samples were wild type for BRAF, suggesting a mutual exclusivity for these mutations. Functional analysis of the MAP3K5 R256C mutation revealed attenuation of MKK4 (mitogen-activated protein kinase kinase 4) activation through increased binding of the inhibitory protein thioredoxin (TXN/TRX-1/Trx), resulting in increased proliferation and anchorage-independent growth of melanoma cells. This mutation represents a potential target for the design of new therapies to treat melanoma.

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