Human rgr: transforming activity and alteration in T-cell malignancies

Leonardi, Peter; Kassin, Ezra; Hernández-Muñoz, Inmaculada; Díaz, Roberto; Inghirami, Giorgio; Pellicer, A.

doi:10.1038/sj.onc.1205694

Cited by 13 publications

(23 citation statements)

References 11 publications

(11 reference statements)

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“…Recently, the human orthologue of Rgr, hrgr, has been associated with human T-cell malignancies (7). Similar to rabbit Rgr, which was found as one of the components of a fusion protein isolated from a rabbit squamous cell carcinoma, truncation of hrgr confers transforming properties to its cDNA.…”

Section: Rgr and P15mentioning

confidence: 99%

“…Mutations in the Rgr human orthologue, hrgr, have been associated with human T-cell malignancies (7). In contrast, MSV-RGR transgenic mice expressing low levels of Rgr in lymphoid tissues (data not shown) are prone to splenic lymphomas in a p15…”

Section: The Histopathological Analysis Of the Fibrosarcomas Obtainedmentioning

confidence: 99%

“…The remaining GEFs, although they are not transforming, cooperate with activated Raf in focus formation processes (2,28). Unlike in mouse cells, the RalGEF pathway has been reported to be important for Ras-mediated transformation in human cells (7,29). In vivo studies have shown previously that activation of RalGEF is sufficient to initiate an invasive phenotype in nude mice (30).…”

Section: Rgr Is the First Ral Guanine Nucleotide Exchange Factormentioning

confidence: 99%

“…Indeed, a DNA rearrangement has been found within the hrgr gene in a human anaplastic large cell lymphoma cell line (DHL; Ref. 7). It is interesting to point out that chromosomal translocations frequently have been associated with sarcomagenesis (48), and in many cases, these Fig.…”

Section: Rgr and P15mentioning

confidence: 99%

“…This overexpression resulted in subsequent Ras activation (6). The human orthologue of the rabbit Rgr gene, hrgr, has been recently isolated from lymphoid malignant cell lines that express several hrgr mutant transcripts (7). Similar to the activated rabbit truncated form (Rgr oncogene), the human mutant transcripts found in T-cell lines and some T-cell lymphomas are truncated forms of the hrgr gene (7).…”

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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Section: Rgr and P15mentioning

confidence: 99%

Section: The Histopathological Analysis Of the Fibrosarcomas Obtainedmentioning

confidence: 99%

Section: Rgr Is the First Ral Guanine Nucleotide Exchange Factormentioning

confidence: 99%

Section: Rgr and P15mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The Rgr Oncogene Induces Tumorigenesis in Transgenic Mice

et al. 2004

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RalA is overactivated in medulloblastoma

et al. 2016

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Medulloblastoma (MDB) represents a major form of malignant brain tumors in the pediatric population. A vast spectrum of research on MDB has advanced our understanding of the underlying mechanism, however, a significant need still exists to develop novel therapeutics on the basis of gaining new knowledge about the characteristics of cell signaling networks involved. The Ras signaling pathway, one of the most important proto-oncogenic pathways involved in human cancers, has been shown to be involved in the development of neurological malignancies. We have studied an important effector down-stream of Ras, namely RalA (Ras-Like), for the first time and revealed overactivation of RalA in MDB. Affinity precipitation analysis of active RalA (RalA-GTP) in eight MDB cell lines (DAOY, RES256, RES262, UW228-1, UW426, UW473, D283 and D425) revealed that the majority contained elevated levels of active RalA (RalA-GTP) as compared with fetal cerebellar tissue as a normal control. Additionally, total RalA levels were shown to be elevated in 20 MDB patient samples as compared to normal brain tissue. The overall expression of RalA, however, was comparable in cancerous and normal samples. Other important effectors of RalA pathway including RalA binding protein-1 (RalBP1) and protein phosphatase A (PP2A) down-stream of Ral and Aurora kinase A (AKA) as an upstream RalA activator were also investigated in MDB. Considering the lack of specific inhibitors for RalA, we used gene specific silencing in order to inhibit RalA expression. Using a lentivirus expressing anti-RalA shRNA we successfully inhibited RalA expression in MDB and observed a significant reduction in proliferation and invasiveness. Similar results were observed using inhibitors of AKA and geranyl-geranyl transferase (non-specific inhibitors of RalA signaling) in terms of loss of in vivo tumorigenicity in heterotopic nude mouse model. Finally, once tested in cells expressing CD133 (a marker for MDB cancer stem cells), higher levels of RalA activation was observed. These data not only bring RalA to light as an important contributor to the malignant phenotype of MDB but introduces this pathway as a novel target in the treatment of this malignancy.

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The RAL signaling network: Cancer and beyond

Apken

Oeckinghaus

2021

International Review of Cell and Molecular Biology

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Human rgr: transforming activity and alteration in T-cell malignancies

Cited by 13 publications

References 11 publications

The Rgr Oncogene Induces Tumorigenesis in Transgenic Mice

The Rgr Oncogene Induces Tumorigenesis in Transgenic Mice

RalA is overactivated in medulloblastoma

The RAL signaling network: Cancer and beyond

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