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, v-Rel, the acutely transforming member of this family, induces the rapid transformation of lymphocytes in vitro and in experimental animals. The v-Rel system has provided an excellent model to identify the mechanisms of oncogenesis by Rel/NF-_:B proteins, v-Rel transforms cells by deregulating the expression of genes normally controlled by Rel/NF-rd3 family members. The identification and characterization of target genes differentially regulated by v-Rel will, therefore, provide insight into the molecular mechanisms by which Rel/NF-x.B proteins function in tumorigenesis. Recent studies in this laboratory have identified a number of genes that are transcriptionally activated by v-Rel and whose expression contributes to the transformation process, ch-IAP1, a member of the inhibitor-of-apoptosis family, and IRF-4, an interferon regulatory factor, are upregulated in fibroblasts and lymphoid cells transformed by v-Rel. Expression of either protein enhances the ability of v-Rel to transform lymphocytes. By contrast, expression of ch-IAP1 or IRF-4 in the antisense orientation reduces the transforming ability of v-Rel. In addition to these proteins, Bcl-2 components and other members of the IRF family are differentially regulated by oncogenic Rel proteins. These proteins have established functions in the regulation of cell proliferation and apoptosis in lymphoid cells. The efficient transformation of cells by v-Rel appears to result from its ability to protect cells from apoptosis and interfere with the regulation of growth. The goals of this study are to define the mechanisms by which v-Rel target genes contribute to cell transformation. The role of ch-IAP1 in Rel-mediated transformation will be established by retrovirus-mediated gene expression and antisense techniques. The functional domains in ch-IAP1 required for its transforming and apoptosis-suppressing functions will be mapped, ch-IAP I knockout B cell lines will be generated to define the requirement of this protein for the inhibition of apoptosis by v-Rel. Additional studies will define whether the differential activation of genes by v-Rel and a B cell tropic variant (S2A3v-Rel) can account for the target cell specificity of these oncogenes. Contributions of Bcl-2 and IRF family members to cell transformation by v-Rel and S2A3v-Rel will be defined. Finally, experiments will examine the mechanisms by which IRF-4 activates cell proliferation and extends the life span of cells transformed by v-Rel. These studies on the mechanisms of oncogenesis by v-Rel will provide insight into the contributions of Rel/NF-KB proteins in tumorigenesis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA098151-05
Application #
7161474
Study Section
Pathology B Study Section (PTHB)
Program Officer
Read-Connole, Elizabeth Lee
Project Start
2003-01-01
Project End
2008-12-31
Budget Start
2007-01-15
Budget End
2008-12-31
Support Year
5
Fiscal Year
2007
Total Cost
$243,037
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
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
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
Kim, Yeryung; Kim, Hyemin; Yoo, Hae-Young et al. (2011) Suppression of CFTR-mediated Cl secretion of airway epithelium in vitamin C-deficient mice. J Korean Med Sci 26:317-24
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
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