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The human Rgr oncogene is overexpressed in T-cell malignancies and induces transformation by acting as a GEF for Ras and Ral

Oncogene volume 30, pages 3661–3671 (2011)Cite this article

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Abstract

The Ras superfamily of GTPases is involved in the modification of many cellular processes including cellular motility, proliferation and differentiation. Our laboratory has previously identified the RalGDS-related (Rgr) oncogene in a DMBA (7,12-dimethylbenz[α]anthracene)-induced rabbit squamous cell carcinoma and its human orthologue, hRgr. In this study, we analyzed the expression levels of the human hRgr transcript in a panel of human hematopoietic malignancies and found that a truncated form (diseased-truncated (Dtr-hrgr)) was significantly overexpressed in many T-cell-derived neoplasms. Although the Rgr proto-oncogene belongs to the RalGDS family of guanine nucleotide exchange factors (GEFs), we show that upon the introduction of hRgr into fibroblast cell lines, it is able to elicit the activation of both Ral and Ras GTPases. Moreover, in vitro guanine nucleotide exchange assays confirm that hRgr promotes Ral and Ras activation through GDP dissociation, which is a critical characteristic of GEF proteins. hRgr has guanine nucleotide exchange activity for both small GTPases and this activity was reduced when a point mutation within the catalytic domain (CDC25) of the protein, (cd) Dtr-hRgr, was utilized. These observations prompted the analysis of the biological effects of hRgr and (cd) hRgr expression in cultured cells. Here, we show that hRgr increases proliferation in low serum, increases invasion, reduces anchorage dependence and promotes the progression into the S phase of the cell cycle; properties that are abolished or severely reduced in the presence of the catalytic dead mutant. We conclude that the ability of hRgr to activate both Ral and Ras is responsible for its transformation-inducing phenotype and it could be an important contributor in the development of some T-cell malignancies.

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Acknowledgements

We are grateful to Drs M Philips, D Bar-Sagi and J Bos for the gift of expression plasmids. We thank Kamlesh Yadav and Pamela Sung for their assistance with the mant-guanine nucleotide exchange and cellular proliferation assays, respectively, and Dr M Liu for her assistance with the statistical analysis for the cellular proliferation assay. These studies were supported by NIH Grants CA50434 and CA36327 to AP.

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  1. L Martello

    Present address: 3Current address: Division of Gastroenterology and Hepatology, SUNY Downstate Medical Center, New York, NY, USA,

Authors and Affiliations

  1. Department of Pathology, New York University Langone Medical Center, New York, NY, USA

    K Osei-Sarfo, L Martello & A Pellicer

  2. Department of Hematopathology, New York University Langone Medical Center, New York, NY, USA

    S Ibrahim

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Correspondence to A Pellicer.

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Osei-Sarfo, K., Martello, L., Ibrahim, S. et al. The human Rgr oncogene is overexpressed in T-cell malignancies and induces transformation by acting as a GEF for Ras and Ral. Oncogene 30, 3661–3671 (2011). https://doi.org/10.1038/onc.2011.93

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