Regulatory mechanisms controlling expression of the human B-ATF gene
Abstract
Our laboratory isolated a cDNA encoding a novel basic leucine zipper (bZIP) transcription factor called B-ATF from a human Epstein-Barr virus (EBV) immortalized B cell cDNA library. Using B-ATF as a bait in a yeast two hybrid library screen, we isolated several dimerization partners for B-ATF, Including the JunB proto-oncoprotein. B-ATF forms stable heterodimers with the Jun proteins to bind to AP-1 DNA sites. However, unlike the transcriptionally active Fos/Jun heterodimer, which comprises the bulk of AP-1 binding activity in growing cells, a B-ATF/Jun heterodimer is transcriptionally inert and cannot activate AP-1 reporter gene expression. Northern blot analysis of poly A+ mRNA isolated from various human tumor cell lines shows prominent expression of B-ATF in Raji cells, an EBV positive Burkitt's lymphoma cell line. The elevated level of B-ATF mRNA in Raji cells, coupled with the original isolation of the B-ATF cDNA from an EBV immortalized B cell library, prompted the laboratory to examine if B-ATF is up-regulated following EBV infection. Using reverse transcription polymerase chain reaction (RT-PCR) analysis to detect B-ATF mRNA expression, there is a 25-fold induction of B-ATF mRNA within 24 hours following infection with EBV. Moreover, B-ATF also has been shown to be a cellular target of the human T cell leukemia virus (HTLV-1). Both EBV and HTLV-1 are causative agents for lymphocytic proliferative disorders. Given the putative role of B-ATF as a suppresser of AP-1. a complex ordinarily associated with cellular growth, it is unclear why B-ATF is up-regulated by of both these viruses. The genomic B-ATF clone recently has been isolated and will provide a unique tool to dissect how viral products lead to the up-regulation of cellular genes. The identification of cis-acting DNA elements in the human B-ATF gene that respond to EBV and HTLV-1, in conjunction with studies on the function of the B-ATF protein in mammalian cells, may identify additional pathways through which EBV and HTLV-1 lead to cellular immortalization and may define targets to manipulate uncontrolled proliferation.
Degree
Ph.D.
Advisors
Taparowsky, Purdue University.
Subject Area
Molecular biology
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