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- Christin E. Burd
- 1Department of Molecular Genetics, The Ohio State University, Columbus, Ohio.
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- Wenjin Liu
- 3Department of Genetics, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
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- Minh V. Huynh
- 5Department of Biochemistry and Biophysics, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
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- Meriam A. Waqas
- 1Department of Molecular Genetics, The Ohio State University, Columbus, Ohio.
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- James E. Gillahan
- 1Department of Molecular Genetics, The Ohio State University, Columbus, Ohio.
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- Kelly S. Clark
- 3Department of Genetics, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
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- Kailing Fu
- 3Department of Genetics, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
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- Brit L. Martin
- 1Department of Molecular Genetics, The Ohio State University, Columbus, Ohio.
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- William R. Jeck
- 3Department of Genetics, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
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- George P. Souroullas
- 3Department of Genetics, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
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- David B. Darr
- 3Department of Genetics, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
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- Daniel C. Zedek
- 6Department of Dermatology, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
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- Michael J. Miley
- 7Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
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- Bruce C. Baguley
- 8Auckland Cancer Society Research Centre, University of Auckland, Auckland, New Zealand.
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- Sharon L. Campbell
- 4The Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
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- Norman E. Sharpless
- 3Department of Genetics, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
説明
<jats:title>Abstract</jats:title> <jats:p>NRAS mutation at codons 12, 13, or 61 is associated with transformation; yet, in melanoma, such alterations are nearly exclusive to codon 61. Here, we compared the melanoma susceptibility of an NrasQ61R knock-in allele to similarly designed KrasG12D and NrasG12D alleles. With concomitant p16INK4a inactivation, KrasG12D or NrasQ61R expression efficiently promoted melanoma in vivo, whereas NrasG12D did not. In addition, NrasQ61R mutation potently cooperated with Lkb1/Stk11 loss to induce highly metastatic disease. Functional comparisons of NrasQ61R and NrasG12D revealed little difference in the ability of these proteins to engage PI3K or RAF. Instead, NrasQ61R showed enhanced nucleotide binding, decreased intrinsic GTPase activity, and increased stability when compared with NrasG12D. This work identifies a faithful model of human NRAS-mutant melanoma, and suggests that the increased melanomagenecity of NrasQ61R over NrasG12D is due to heightened abundance of the active, GTP-bound form rather than differences in the engagement of downstream effector pathways.</jats:p> <jats:p>Significance: This work explains the curious predominance in human melanoma of mutations of codon 61 of NRAS over other oncogenic NRAS mutations. Using conditional “knock-in” mouse models, we show that physiologic expression of NRASQ61R, but not NRASG12D, drives melanoma formation. Cancer Discov; 4(12); 1418–29. ©2014 AACR.</jats:p> <jats:p>This article is highlighted in the In This Issue feature, p. 1355</jats:p>
収録刊行物
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- Cancer Discovery
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Cancer Discovery 4 (12), 1418-1429, 2014-12-01
American Association for Cancer Research (AACR)