Targeted deletion of RasGRP1 impairs skin tumorigenesis.
Ras is frequently activated in cutaneous squamous cell carcinoma, a prevalent form of skin cancer. However, the pathways that contribute to Ras-induced transformation have not been entirely elucidated. We have previously demonstrated that in transgenic mice, overexpression of the Ras activator RasGRP1 promotes the formation of spontaneous skin tumors and enhances malignant progression in the multistage carcinogenesis skin model that relies on the oncogenic activation of H-Ras. Utilizing a RasGRP1 knockout mouse model (RasGRP1 KO), we now show that lack of RasGRP1 reduced the susceptibility to skin tumorigenesis. The dependency on RasGRP1 was associated with a diminished response to the phorbol ester tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). Specifically, we found impairment of epidermal hyperplasia induced by TPA through keratinocyte proliferation. Using a keratinocyte cell line that carries a ras oncogenic mutation, we also demonstrated that RasGRP1 could further activate Ras in response to TPA. Thus, we propose that RasGRP1 upregulates signaling from Ras and contributes to epidermal tumorigenesis by increasing the total dosage of active Ras.
Cancer Biology Program, University of Hawaii Cancer Center, University of Hawaii at Manoa, Honolulu, HI 96813, USA.
Amrish
A
Sharma
Lauren L
LL
Fonseca
Cynthia
C
Rajani
Jodi K
JK
Yanagida
Yuka
Y
Endo
J Mark
JM
Cline
James C
JC
Stone
Junfang
J
Ji
Joe W
JW
Ramos
Patricia S
PS
Lorenzo
D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism; D003062:Codon; D017353:Gene Deletion; D018390:Gene Targeting; D011905:Genes, ras; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics*; D006965:Hyperplasia / Q000188:drug therapy / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D012867:Skin / Q000378:metabolism* / Q000473:pathology; D012878:Skin Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D013755:Tetradecanoylphorbol Acetate / Q000009:adverse effects; D015533:Transcriptional Activation / Q000187:drug effects
D003062:Codon; D020662:Guanine Nucleotide Exchange Factors; C112278:Rasgrp1 protein, mouse; D013755:Tetradecanoylphorbol Acetate