TY - JOUR
T1 - Somatic mutations in MAP3K5 attenuate its proapoptotic function in melanoma through increased binding to thioredoxin
AU - Prickett, Todd D.
AU - Zerlanko, Brad
AU - Gartner, Jared J.
AU - Parker, Stephen C.J.
AU - Dutton-Regester, Ken
AU - Lin, Jimmy C.
AU - Teer, Jamie K.
AU - Wei, Xiaomu
AU - Jiang, Jiji
AU - Chen, Guo
AU - Davies, Michael A.
AU - Gershenwald, Jeffrey E.
AU - Robinson, William
AU - Robinson, Steven
AU - Hayward, Nicholas K.
AU - Rosenberg, Steven A.
AU - Margulies, Elliott H.
AU - Samuels, Yardena
N1 - Funding Information:
We thank Dr U Rudloff for acquiring tumor specimens, Drs Chris Schmidt and Peter Parsons for establishment of the majority of melanoma cell lines, and Drs V. Maduro, H. Abaan, and P. Cruz for generating the sequence data analyzed here. We thank Dr V.G. Prieto for pathologic review of the biospecimens from the Melanoma Informatics, Tissue Resource, and Pathology Core (MelCore) at M.D. Anderson. We thank Dr T. Wolfsberg for bioinformatics help, and J. Fekecs and D. Leja for graphical assistance. This work was supported by the Intramural Research Programs of the National Human Genome Research Institute, the National Cancer Institute (R21CA152432 to RK), National Institutes of Health, USA, The University of Texas MD Anderson Cancer Center Melanoma SPORE (P50 CA93459), the National Health and Medical Research Council of Australia, and by a public/private partnership between the Intramural Research Programs of the National Human Genome Research Institute, the National Cancer Institute, and Eli Lilly and Company coordinated by the Foundation for the National Institutes of Health. YS is supported by the Israel Science Foundation grant numbers 1604/13 and 877/13, a research grant from the Peter and Patricia Gruber Awards, and the ERC (StG-335377).
PY - 2014/2/1
Y1 - 2014/2/1
N2 - 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.
AB - 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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U2 - 10.1038/jid.2013.365
DO - 10.1038/jid.2013.365
M3 - Article
C2 - 24008424
AN - SCOPUS:84892810694
SN - 0022-202X
VL - 134
SP - 452
EP - 460
JO - Journal of Investigative Dermatology
JF - Journal of Investigative Dermatology
IS - 2
ER -