The Rgr oncogene (homologous to RalGDS) induces transformation and gene expression by activating Ras, Ral and Rho mediated pathways

Hernández-Muñoz, Inmaculada; Malumbres, Marcos; Leonardi, Peter; Pellicer, A.

doi:10.1038/sj.onc.1203586

Cited by 25 publications

(24 citation statements)

References 54 publications

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“…In addition, C3-like ADP-ribosyltransferases interact non-enzymatically with Ral without ADP-ribosylating the GTPase (Wilde et al 2002a;Pautsch et al 2005). Ral belongs to the Ras branch of low molecular GTPases and is involved in transcriptional activation (Hernandez-Munoz et al 2000), Ras-mediated cell transformation Urano et al 1996), vesicle trafficking (Shen et al 2001) and cytoskeletal rearrangements (Jullien-Flores et al 1995;Ohta et al 1999).…”

Section: Non-enzymatic Interaction Of C3-like Exoenzymes With Ralmentioning

confidence: 99%

C3 exoenzymes, novel insights into structure and action of Rho-ADP-ribosylating toxins

Vogelsgesang

Pautsch

Aktories

2006

Naunyn-Schmied Arch Pharmacol

100

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The family of C3-like exoenzymes comprises seven bacterial ADP-ribosyltransferases of different origin. The common hallmark of these exoenzymes is the selective N-ADP-ribosylation of the low molecular mass GTPbinding proteins RhoA, B, and C and inhibition of signal pathways controlled by Rho GTPases. Therefore, C3-like exoenzymes were applied as pharmacological tools for analyses of cellular functions of Rho protein in numerous studies. Recent structural and functional analyses of C3-like exoenzymes provide detailed information on the molecular mechanisms and functional consequences of ADP-ribosylation catalyzed by these toxins. More recently additional non-enzymatic actions of C3-like ADP-ribosyltransferases have been identified showing that C3 transferases from Clostridium botulinum and Clostridium limosum form a GDI-like complex with the Ras-like low molecular mass GTPase Ral without ADP-ribosylation. These results add novel information on the molecular mode of action(s) of C3-like exoenzymes and are discussed in this review.

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Section: Non-enzymatic Interaction Of C3-like Exoenzymes With Ralmentioning

confidence: 99%

C3 exoenzymes, novel insights into structure and action of Rho-ADP-ribosylating toxins

Vogelsgesang

Pautsch

Aktories

2006

Naunyn-Schmied Arch Pharmacol

100

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“…These partially transformed phenotypes induced by distinct Ras e ectors in rodent cells are strikingly similar to the partially transformed phenotypes induced by Jun : Fra2 and Jun : ATF2 in avian ®broblasts. Interestingly, activation of the Raf-MEK-ERK pathway strongly induces c-Jun : Fra1 and c-Jun : Fra2 activity in rodent ®broblasts (Cook et al, 1999; Figure 1), while Rasdependent phosphorylation of c-Jun-Ser63/73 is established via the RalGEF e ector pathway (de Ruiter et al, 2000;Hernandez-Munoz et al, 2000). Moreover, Rlf-caax, an active, membrane targeted, version of the Ral exchange factor Rlf induces c-Jun : ATF2 rather than c-Jun : Fos activity in these ®broblasts (van Dam et al, unpublished).…”

Section: Repression Of Cellular Genes By Atf3 In Cefsmentioning

confidence: 99%

Distinct roles of Jun : Fos and Jun : ATF dimers in oncogenesis

2001

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“…In addition, Rgr also enhanced the phosphorylation of extracellular signal-regulated kinases, p38, and c-Jun-NH 2 -terminal kinases. The biological significance of these activities was confirmed using dominant-negative forms of Ras, Ral, and Rho that blocked the transcriptional activation induced by Rgr (3). Interestingly, only the dominant-negative form of Ras inhibited Rgr transformation, indicating that Ras activation is crucial for the oncogenic activity of Rgr (3).…”

Section: Introductionmentioning

confidence: 78%

“…Rgr lacks the Ras-interacting domain within the COOH-terminal end present in other family members. Interestingly, its introduction into cells resulted in increased levels of GTP-bound Ras (3). Moreover, Rgr is the first member of the Ral-mediated pathway to display tumorigenic properties as demonstrated by the potent tumorigenic activity of Rgr in the nude mice assay (1) and the formation of transformed foci and abnormal cellular morphologies in cultured cells (3).…”

Section: Introductionmentioning

confidence: 99%

“…Interestingly, its introduction into cells resulted in increased levels of GTP-bound Ras (3). Moreover, Rgr is the first member of the Ral-mediated pathway to display tumorigenic properties as demonstrated by the potent tumorigenic activity of Rgr in the nude mice assay (1) and the formation of transformed foci and abnormal cellular morphologies in cultured cells (3). In addition, Rgr also enhanced the phosphorylation of extracellular signal-regulated kinases, p38, and c-Jun-NH 2 -terminal kinases.…”

Section: Introductionmentioning

confidence: 99%

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The Rgr Oncogene Induces Tumorigenesis in Transgenic Mice

et al. 2004

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To study the oncogenic potential of Rgr in vivo, we have generated several transgenic Rgr mouse lines, which express the oncogene under the control of different promoters. These studies revealed that Rgr expression leads to the generation of various pathological alterations, including fibrosarcomas, when its transgenic expression is restricted to nonlymphoid tissues. Moreover, the overall incidence and latency of fibrosarcomas were substantially increased and shortened, respectively, in a p15INK4b -defective background. More importantly, we also have demonstrated that Rgr expression in thymocytes of transgenic mice induces severe alterations in the development of the thymocytes, which eventually lead to a high incidence of thymic lymphomas. This study demonstrates that oncogenic Rgr can induce expression of p15INK4b and, more importantly, that both Rgr and p15INK4b cooperate in the malignant phenotype in vivo. These findings provide new insights into the tumorigenic role of Rgr as a potent oncogene and show that p15INK4b can act as a tumor suppressor gene.

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The Rgr oncogene (homologous to RalGDS) induces transformation and gene expression by activating Ras, Ral and Rho mediated pathways

Cited by 25 publications

References 54 publications

C3 exoenzymes, novel insights into structure and action of Rho-ADP-ribosylating toxins

C3 exoenzymes, novel insights into structure and action of Rho-ADP-ribosylating toxins

Distinct roles of Jun : Fos and Jun : ATF dimers in oncogenesis

The Rgr Oncogene Induces Tumorigenesis in Transgenic Mice

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