The v-Rel oncoprotein encoded by reticuloendotheliosis virus (REV-T) rapidly transforms lymphocytes in vitro and induces an invariably fatal lymphoproliferative disorder in experimental animals. v-Rel is the most oncogenic member of the Rel/NF-KB family and transforms cells by deregulating the expression of genes normally controlled by cellular Rel/NF-KB proteins. Rel/NF-KB proteins are transcription factors that play a central role in the regulation of cell proliferation, apoptosis, and immune responses. The altered or aberrant expression of Rel/NF-KB proteins is implicated in the pathology of human cancers derived from a variety of tissues. The identification and characterization of target genes differentially regulated by v-Rel, therefore, will provide insight into the mechanisms of tumorigenesis by Rel/NF-KB proteins. Studies in this laboratory have focused on the identification of genes that are transcriptionally regulated by v-Rel and contribute to the transformation process. Previous studies have established that AP-1 transcription factors are required for the full transforming potential of v-Rel. AP-1 is stimulated by mitogen- activated protein kinase (MAPK) pathways, and a correlation has been established between activation of JNK and ERK MAPKs and the maintenance of the transformed state by v-Rel. The contributions of MAPK components to cell transformation by v-Rel will be analyzed by the activation or suppression of MAPK pathways through the use of MAPK mutants, chemical inhibitors, and siRNAs. Upstream activators and downstream effectors of MAPKs identified by microarray analysis will be studied to determine how these pathways function in v-Rel-mediated transformation Unlike other identified v-Rel target genes, shSbgrl provides the first example of a gene downregulated by v-Rel that suppresses oncogenic cell transformation. Although the function(s) of SH3BGRL family members are unknown, an intact SH3-binding domain is required for its ability to interfere with v-Rel-mediated cell transformation. Biochemical and genomic approaches will be used to identify proteins that interact with SH3BGRL to gain insight into the mechanism(s) by which it inhibits cell transformation by v-Rel. Promoter analysis and chromatin remodeling studies will define the mechanisms by which v-Rel suppresses expression of shdbgrl. Finally, we have shown that telomerase is activated during transformationof lymphoid cells by v-Rel and that inhibition of telomerase activity rapidly leads to apoptosis. Telomerase activity is largely controlled through the regulation of the TERT subunit, and cells transformed by v-Rel exhibit a 10-fold increase in the levels of TERT mRNA. Alternative splicing of TERT is suppressed in v-Rel transformed cells, resulting in an increased proportion of TERT transcripts encoding proteins, relative to those of splenic lymphocytes. Proposed experiments will investigate the regulation of the TERT promoter by v-Rel, define the telomerase activity encoded by TERT splice variants, and determine the mechanism by which v-Rel suppresses the alternative splicing of TERT.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Virology - B Study Section (VIRB)
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Read-Connole, Elizabeth Lee
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University of Texas Austin
Schools of Arts and Sciences
United States
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Hrdli?ková, Radmila; Nehyba, Ji?í; Bargmann, William et al. (2014) Multiple tumor suppressor microRNAs regulate telomerase and TCF7, an important transcriptional regulator of the Wnt pathway. PLoS One 9:e86990
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