Final published version
Research output: Contribution to Journal/Magazine › Journal article › peer-review
Research output: Contribution to Journal/Magazine › Journal article › peer-review
}
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 -