This is a chronological listing of grants held by this department, with the most recent listed first. New grants appear in this list weekly and contribute related to the department's Research Profile. The source of grants for this application comes directly from your institution.
Regulation of HTLV-1 and cellualar gene transcription by the viral protein HBZ
Isabelle Lemasson4/1/2010 - 3/31/2015
|Sponsoring Organization:||National Institutes of Health (NIH)|
|Awarding Organization Is:||Eastern Carolina University|
Isabelle Lemasson (Lead Principal Investigator)
Human T-cell leukemia virus type 1 (HTLV-1) is a complex retrovirus that is the causative agent of a variety of clinical disorders including adult T-cell leukemia (ATL), an aggressive and often fatal malignancy of mature activated T-cells. ATL is frequently diagnosed after several decades of infection, suggesting that a long period of viral latency contributes to the development of disease. The HTLV-1 basic leucine zipper factor (HBZ) is believed to play a role in viral latency. This protein is localized in the nucleus and carries a basic leucine zipper (bZIP) domain that promotes protein dimerization through interactions with corresponding bZlP domains in certain cellular transcription factors, including CREB-2, c-Jun, JunB and JunD. We found that HBZ also interacts with the bZlP factors ATF-1, CREB and CREM. With the potential exception of JunD, interactions with HBZ repress transcription by preventing factors from binding to DNA. HBZ also contains an activation domain that we found to bind to the cellular coactivators, p300 and CBP. As many of these cellular proteins stimulate HTLV-1 transcription, interactions with HBZ lead to an inhibition of viral transcription. This effect and repression of HTLV-1 transcription through other mechanisms is unlikely to repress HBZ expression since its gene is uniquely encoded on the minus strand of the provirus and is not transcribed from the 5' LTR. HBZ has also been found to deregulate the expression of a many cellular genes. Currently, the contributions of HBZ interactions with transcriptional regulators to changes in gene expression are largely undefined. We propose to characterize these interactions and their effects on the transcription of cellular genes. In Aim 1, we will investigate interactions between HBZ and cellular bZlP transcription factors and analyze how HBZ affects transcription mediated by these factors. In Aim 2, we propose to dissect the interaction between HBZ and the coactivators p300 and CBP, and determine the role of these interactions in HBZ-mediated deregulation of cellular gene expression. In Aim 3, we propose to identify DNA-binding sites for HBZ and determine whether HBZ activates transcription from these sites. In characterizing HBZ-mediated effects on the transcription of cellular genes, we believe that these studies will help elucidate the cellular processes that are disrupted by HBZ, which will ultimately define the contribution of HBZ to the development of ATL.