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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA033192-24
Application #
8006435
Study Section
Virology - B Study Section (VIRB)
Program Officer
Read-Connole, Elizabeth Lee
Project Start
1984-01-01
Project End
2013-01-31
Budget Start
2011-02-01
Budget End
2013-01-31
Support Year
24
Fiscal Year
2011
Total Cost
$292,972
Indirect Cost
Name
University of Texas Austin
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
170230239
City
Austin
State
TX
Country
United States
Zip Code
78712
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Hrdlickova, Radmila; Nehyba, Jiri; Lim, Shu Ly et al. (2012) Insights into the evolution of mammalian telomerase: platypus TERT shares similarities with genes of birds and other reptiles and localizes on sex chromosomes. BMC Genomics 13:216
Hrdlickova, Radmila; Nehyba, Jiri; Bose Jr, Henry R (2012) Alternatively spliced telomerase reverse transcriptase variants lacking telomerase activity stimulate cell proliferation. Mol Cell Biol 32:4283-96
Tiwari, Richa; Bargmann, William; Bose Jr, Henry R (2011) Activation of the TGF-ýý/Smad signaling pathway in oncogenic transformation by v-Rel. Virology 413:60-71
Liss, A S; Tiwari, R; Kralova, J et al. (2010) Cell transformation by v-Rel reveals distinct roles of AP-1 family members in Rel/NF-kappaB oncogenesis. Oncogene 29:4925-37
Kralova, J; Sheely, J I; Liss, A S et al. (2010) ERK and JNK activation is essential for oncogenic transformation by v-Rel. Oncogene 29:6267-79
Nehyba, Jiri; Hrdlickova, Radmila; Bose, Henry R (2009) Dynamic evolution of immune system regulators: the history of the interferon regulatory factor family. Mol Biol Evol 26:2539-50
Hrdlickova, Radmila; Nehyba, Jiri; Bose Jr, Henry R (2009) Regulation of telomerase activity by interferon regulatory factors 4 and 8 in immune cells. Mol Cell Biol 29:929-41
Tong, S; Liss, A S; You, M et al. (2007) The activation of TC10, a Rho small GTPase, contributes to v-Rel-mediated transformation. Oncogene 26:2318-29
Hrdlickova, Radmila; Nehyba, Jiri; Liss, Andrew S et al. (2006) Mechanism of telomerase activation by v-Rel and its contribution to transformation. J Virol 80:281-95

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