Resistance of R-Ras knockout mice to skin tumour induction.

Ulrike May,Tero A H Järvinen,Katriina Nieminen,Anni M Laitinen,Hannele Uusitalo-Järvinen,Maria Vähätupa,Stuart Prince

doi:10.1038/srep11663

Ulrike May, Tero A H Järvinen + Show 5 more

Open Access

https://doi.org/10.1038/srep11663

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Abstract

The R-ras gene encodes a small GTPase that is a member of the Ras family. Despite close sequence similarities, R-Ras is functionally distinct from the prototypic Ras proteins; no transformative activity and no activating mutations of R-Ras in human malignancies have been reported for it. R-Ras activity appears inhibitory towards tumour proliferation and invasion, and to promote cellular quiescence. Contrary to this, using mice with a deletion of the R-ras gene, we found that R-Ras facilitates DMBA/TPA-induced skin tumour induction. The tumours appeared in wild-type (WT) mice on average 6 weeks earlier than in R-Ras knockout (R-Ras KO) mice. WT mice developed almost 6 times more tumours than R-Ras KO mice. Despite strong R-Ras protein expression in the dermal blood vessels, no R-Ras could be detected in the epidermis from where the tumours arose. The DMBA/TPA skin tumourigenesis-model is highly dependent upon inflammation, and we found a greatly attenuated skin inflammatory response to DMBA/TPA-treatment in the R-Ras KO mice in the context of leukocyte infiltration and proinflammatory cytokine expression. Thus, these data suggest that despite its characterised role in promoting cellular quiescence, R-Ras is pro-tumourigenic in the DMBA/TPA tumour model and important for the inflammatory response to DMBA/TPA treatment.

Highlights

R-Ras is a small GTPase of the Ras family of known oncogenes that was originally identified as a close homolog of oncogenic H-Ras[1]
Our study indicated an important role of the small GTPase R-Ras in epidermal hyperplasia and tumour induction in a skin carcinogenesis-tumour model
Our finding is novel in the sense that we could not detect any R-Ras protein expression in the epidermis, from where the tumours arose, only in the dermal blood vessels (Fig. 2)

Summary

Introduction

R-Ras is a small GTPase of the Ras family of known oncogenes that was originally identified as a close homolog of oncogenic H-Ras[1]. Despite its close structural similarity to other members of the Ras-family, the function of R-Ras is distinct from the prototypic Ras proteins (K-, H-, N-Ras)[2]. Whereas a single amino acid mutation can convert other members of the Ras family into oncogenes, the equivalent mutations in R-Ras did not induce transformative activity[3]. To further highlight the apparent non-oncogenic nature of R-Ras, it was recently shown that R-Ras inhibits all landmark features of cancer; proliferation, migration and cell cycle progression in breast cancer cells in vitro[5]. The distinct role of R-Ras among the Ras family extends to cell signaling[2]. R-Ras activity elevates the affinity and avidity of integrins and enhances cell adhesion to the extracellular matrix[7], whereas these effects are antagonised by H-Ras-Raf signaling[8]. We assumed that carcinogen-initiated tumour formation could induce R-Ras expression and we decided to explore the role of R-Ras in a skin epidermal carcinogenesis model (two-stage DMBA/TPA model) in wild-type (WT) and R-Ras knockout mice (R-Ras KO)

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