Mechanism of T cell preferential activity of the T lymphomagenic SL3-3 virus enhancer
LoSardo, Joseph Emanuel
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Retroviral recombination studies established that enhancer sequences within the U3 component of murine leukemia virus (MuLV) long terminal repeats (LTRs) comprise the primary genetic determinant of viral leukemogenicity. MuLV enhancers comprise a series of components to which factors bind to induce transcription. Presumably, the appropriate combination of factors renders a cell a target for viral leukemogenicity. To understand the basis of viral-host cell interactions that underlie leukemogenicity, it is necessary to identify functional elements within viral enhancers and the cellular factors that interact with them.;Analysis of the enhancer of T-lymphomagenic SL3-3 virus has led to the identification of critical elements that confer T cell preferential transcription. They include the consensus element, enhancer CORE motif as well as upstream elements. Insertion of 5 bp between the CORE and upstream elements substantially reduced expression in T cells; however, insertion of 10 bp was much less inhibitory, arguing that there is a helical phasing dependent cooperative interaction between a CORE binding factor and one or more upstream factors.;Multiple factors have been identified that bind to the critical region. Two factors from the nuclei of T cells bind to the core; one of these, S-CBF, an SL3-3 specific core binding factor, is absent in cells where the activity of the SL3-3 CORE was as active as that of the CORE element of non-leukemogenic Akv virus, suggesting the importance of this factor in determining the high level of SL3-3 expression in T cells. Additionally, the product of the ets-1 proto-oncogene binds upstream of the CORE; this site overlaps a binding site for the factor Lvb. The critical region also contains a binding site for the Myb oncoprotein, which when mutated alters expression significantly in T cells. Either or both of these elements may operate in cooperation with the CORE to enhance transcription. The interaction is critical in a subset of T cells, thus T cells recognize the SL3-3 enhancer differently than non-T cells do. It appears then that only certain T cells have the proper compliment of transcription factors for the SL3-3 enhancer to function in a manner that leads to leukemia.