Activated mutant NRas(Q61K) drives aberrant melanocyte signaling, survival, and invasiveness via a Rac1-dependent mechanism

Research output: Contribution to Journal/Magazine › Journal article › peer-review

Published

Standard

Activated mutant NRas(Q61K) drives aberrant melanocyte signaling, survival, and invasiveness via a Rac1-dependent mechanism. / Li, Ang; Ma, Yafeng; Jin, Meng et al.
In: Journal of Investigative Dermatology, Vol. 132, No. 11, 11.2012, p. 2610-2621.

Research output: Contribution to Journal/Magazine › Journal article › peer-review

Harvard

Li, A, Ma, Y, Jin, M, Mason, S, Mort, RL, Blyth, K, Larue, L, Sansom, OJ & Machesky, LM 2012, 'Activated mutant NRas(Q61K) drives aberrant melanocyte signaling, survival, and invasiveness via a Rac1-dependent mechanism', Journal of Investigative Dermatology, vol. 132, no. 11, pp. 2610-2621. https://doi.org/10.1038/jid.2012.186

APA

Li, A., Ma, Y., Jin, M., Mason, S., Mort, R. L., Blyth, K., Larue, L., Sansom, O. J., & Machesky, L. M. (2012). Activated mutant NRas(Q61K) drives aberrant melanocyte signaling, survival, and invasiveness via a Rac1-dependent mechanism. Journal of Investigative Dermatology, 132(11), 2610-2621. https://doi.org/10.1038/jid.2012.186

Vancouver

Li A, Ma Y, Jin M, Mason S, Mort RL, Blyth K et al. Activated mutant NRas(Q61K) drives aberrant melanocyte signaling, survival, and invasiveness via a Rac1-dependent mechanism. Journal of Investigative Dermatology. 2012 Nov;132(11):2610-2621. doi: 10.1038/jid.2012.186

Author

Li, Ang ; Ma, Yafeng ; Jin, Meng et al. / Activated mutant NRas(Q61K) drives aberrant melanocyte signaling, survival, and invasiveness via a Rac1-dependent mechanism. In: Journal of Investigative Dermatology. 2012 ; Vol. 132, No. 11. pp. 2610-2621.

Bibtex

@article{c8a374e780654bd29f934a2af975fc5f,

title = "Activated mutant NRas(Q61K) drives aberrant melanocyte signaling, survival, and invasiveness via a Rac1-dependent mechanism",

abstract = "Around a fifth of melanomas exhibit an activating mutation in the oncogene NRas that confers constitutive signaling to proliferation and promotes tumor initiation. NRas signals downstream of the major melanocyte tyrosine kinase receptor c-kit and activated NRas results in increased signaling via the extracellular signal-regulated kinase (ERK)/MAPK/ERK kinase/mitogen-activated protein kinase (MAPK) pathways to enhance proliferation. The Ras oncogene also activates signaling via the related Rho GTPase Rac1, which can mediate growth, survival, and motility signaling. We tested the effects of activated NRas(Q61K) on the proliferation, motility, and invasiveness of melanoblasts and melanocytes in the developing mouse and ex vivo explant culture as well as in a melanoma transplant model. We find an important role for Rac1 downstream of NRas(Q61K) in mediating dermal melanocyte survival in vivo in mouse, but surprisingly NRas(Q61K) does not appear to affect melanoblast motility or proliferation during mouse embryogenesis. We also show that genetic deletion or pharmacological inhibition of Rac1 in NRas(Q61K) induced melanoma suppresses tumor growth, lymph node spread, and tumor cell invasiveness, suggesting a potential value for Rac1 as a therapeutic target for activated NRas-driven tumor growth and invasiveness.",

keywords = "Animals, Cell Line, Transformed, Cell Movement, Cell Proliferation, Cell Survival, Dermis, Epidermis, Female, Hair Color, Hyperpigmentation, Lymphatic Metastasis, MAP Kinase Signaling System, Melanocytes, Melanoma, Mice, Mice, Inbred C57BL, Mice, Transgenic, Neoplasm Invasiveness, Neoplasm Transplantation, Neuropeptides, Oncogene Protein p21(ras), Organ Culture Techniques, Pregnancy, Skin Neoplasms, rac GTP-Binding Proteins, rac1 GTP-Binding Protein, Journal Article, Research Support, Non-U.S. Gov't",

author = "Ang Li and Yafeng Ma and Meng Jin and Susan Mason and Mort, {Richard L.} and Karen Blyth and Lionel Larue and Sansom, {Owen J.} and Machesky, {Laura M.}",

year = "2012",

month = nov,

doi = "10.1038/jid.2012.186",

language = "English",

volume = "132",

pages = "2610--2621",

journal = "Journal of Investigative Dermatology",

issn = "0022-202X",

publisher = "Nature Publishing Group",

number = "11",

}

RIS

TY - JOUR

T1 - Activated mutant NRas(Q61K) drives aberrant melanocyte signaling, survival, and invasiveness via a Rac1-dependent mechanism

AU - Li, Ang

AU - Ma, Yafeng

AU - Jin, Meng

AU - Mason, Susan

AU - Mort, Richard L.

AU - Blyth, Karen

AU - Larue, Lionel

AU - Sansom, Owen J.

AU - Machesky, Laura M.

PY - 2012/11

Y1 - 2012/11

N2 - Around a fifth of melanomas exhibit an activating mutation in the oncogene NRas that confers constitutive signaling to proliferation and promotes tumor initiation. NRas signals downstream of the major melanocyte tyrosine kinase receptor c-kit and activated NRas results in increased signaling via the extracellular signal-regulated kinase (ERK)/MAPK/ERK kinase/mitogen-activated protein kinase (MAPK) pathways to enhance proliferation. The Ras oncogene also activates signaling via the related Rho GTPase Rac1, which can mediate growth, survival, and motility signaling. We tested the effects of activated NRas(Q61K) on the proliferation, motility, and invasiveness of melanoblasts and melanocytes in the developing mouse and ex vivo explant culture as well as in a melanoma transplant model. We find an important role for Rac1 downstream of NRas(Q61K) in mediating dermal melanocyte survival in vivo in mouse, but surprisingly NRas(Q61K) does not appear to affect melanoblast motility or proliferation during mouse embryogenesis. We also show that genetic deletion or pharmacological inhibition of Rac1 in NRas(Q61K) induced melanoma suppresses tumor growth, lymph node spread, and tumor cell invasiveness, suggesting a potential value for Rac1 as a therapeutic target for activated NRas-driven tumor growth and invasiveness.

AB - Around a fifth of melanomas exhibit an activating mutation in the oncogene NRas that confers constitutive signaling to proliferation and promotes tumor initiation. NRas signals downstream of the major melanocyte tyrosine kinase receptor c-kit and activated NRas results in increased signaling via the extracellular signal-regulated kinase (ERK)/MAPK/ERK kinase/mitogen-activated protein kinase (MAPK) pathways to enhance proliferation. The Ras oncogene also activates signaling via the related Rho GTPase Rac1, which can mediate growth, survival, and motility signaling. We tested the effects of activated NRas(Q61K) on the proliferation, motility, and invasiveness of melanoblasts and melanocytes in the developing mouse and ex vivo explant culture as well as in a melanoma transplant model. We find an important role for Rac1 downstream of NRas(Q61K) in mediating dermal melanocyte survival in vivo in mouse, but surprisingly NRas(Q61K) does not appear to affect melanoblast motility or proliferation during mouse embryogenesis. We also show that genetic deletion or pharmacological inhibition of Rac1 in NRas(Q61K) induced melanoma suppresses tumor growth, lymph node spread, and tumor cell invasiveness, suggesting a potential value for Rac1 as a therapeutic target for activated NRas-driven tumor growth and invasiveness.

KW - Animals

KW - Cell Line, Transformed

KW - Cell Movement

KW - Cell Proliferation

KW - Cell Survival

KW - Dermis

KW - Epidermis

KW - Female

KW - Hair Color

KW - Hyperpigmentation

KW - Lymphatic Metastasis

KW - MAP Kinase Signaling System

KW - Melanocytes

KW - Melanoma

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Transgenic

KW - Neoplasm Invasiveness

KW - Neoplasm Transplantation

KW - Neuropeptides

KW - Oncogene Protein p21(ras)

KW - Organ Culture Techniques

KW - Pregnancy

KW - Skin Neoplasms

KW - rac GTP-Binding Proteins

KW - rac1 GTP-Binding Protein

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1038/jid.2012.186

DO - 10.1038/jid.2012.186

M3 - Journal article

C2 - 22718121

VL - 132

SP - 2610

EP - 2621

JO - Journal of Investigative Dermatology

JF - Journal of Investigative Dermatology

SN - 0022-202X

IS - 11

ER -

Research

Links

Text available via DOI:

Keywords