Date of Award

2009

Degree Type

Dissertation

Department

Biological, Geological and Environmental Sciences

First Advisor

Fontes, Joseph

Subject Headings

Zinc-finger proteins, Major histocompatibility complex -- Genetic aspects, Genetic transcription, Protein-protein interactions, Transcription, Zinc finger proteins, MHC II, Protein-Protein interactions

Abstract

We have identified several protein-protein interactions amongst the members of the zinc finger, X-linked (ZXD) family of proteins (ZXDA, ZXDB, ZXDC and ZXDC2) that have important roles in the regulation of major histocompatibility complex class II and several myeloid-specific genes. The ZXDC and ZXDA proteins share significant nucleotide sequence homology and each contain ten C2H2 zinc fingers and a transcription activation domain. In addition, ZXDC has a C-terminal region that is necessary to interact with a key cofactor, CIITA (Class II transactivator) and activate Major histocompatibility complex class II and class I (MHC II and MHC I respectively) genes. In chapter II we demonstrate that the ZXDC and ZXDA proteins can self-associate, as well as, hetero-associate. Moreover, in vitro studies in our lab revealed that the association of ZXDC with ZXDA is necessary and self-association of neither protein was sufficient to interact with CIITA and thereby activate MHC II gene transcription. In addition to CIITA, we found that ZXDC interacted with two other components of the regulatory factor X complex, namely, RFX5 and RFX-ANK (RFX having ankyrin repeats) which are components of the MHC II enhanceosome. The RFX heterotrimeric complex consisting of RFX5, RFX-AP (RFX-associated protein), RFX-ANK binds to the conserved X1 box of MHC II promoter. The necessity for RFX complex in MHC II gene regulation is underscored by bare lymphocyte syndrome, a genetic disorder which results from mutation in one of the RFX proteins. Our results support for a role of ZXDC-ZXDA heterocomplex to mediate interactions with components of the MHC II enhanceosome thereby enhancing the stability of the complex as a mechanism of activating MHC II gene transcription. Interestingly, the ZXD family of proteins seems to have a broader role in gene regulation. In chapter III we demonstrate that the ZXDC protein interacts and represses the transcriptional activities of two myeloid transcription factors, namely, purine box binding protein PU.1 and Gr

Download

Included in

Biology Commons

COinS