The Rgr Oncogene Induces Tumorigenesis in Transgenic Mice

Abstract

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.

Sindbis viral vectors target hematopoietic malignant cells

“…42 Screening mice for the transgene was performed by PCR of DNA extracted as described, 42 using forward primers specific for the promoter and the reverse primer 907-884 (5 0 -GTGCCTGGCTGCA GGCTCCGCAGG-3 0 ), which is specific for the transgene. The forward primer was as follows: CD4-RGR-F1 (5 0 -GCCCACTTTTGGGT ATCAGA-3 0 ) for the CD4-RGR transgenic lines.…”

Harnessing Functional Genomics to Reverse Chemoresistance in Breast Cancer

“…The mechanistic basis of RalGEF activation is poorly understood; however, a series of observations suggest that one important aspect involves relief of autoinhibitory interactions of amino-terminal and/or C-terminal regulatory motifs (indicated in the figure in yellow and red, respectively) with the catalytic domain (indicated in green). In the case of RGR (a), N-terminal truncation mutants found in lymphoma exhibit cell transformation activity in cell culture 73 and transgenic expression in thymocytes of p15INK4b (also known as Cdkn2b)-defective mice induce a high incidence of thymic lymphomas 74 . Consistently with this regulatory motif, 3-phosphoinositide-dependent protein kinase 1 (PDPK1) associates with the N terminus of RALGDS to relieve autoinhibition of catalytic activity in response to epidermal growth factor receptor activation 75,76. RALGDS is also a direct effector of Ras-GTP through the C-terminal Ras association (RA) domain (b).…”