The DEC1 transcription factor: Oncogenic involvement and molecular mechanisms on transcription regulation
The basic helix-loop-helix (bHLH) proteins are intimately associated with developmental events such as cell differentiation and lineage commitment. The HLH domain in the bHLH motif is responsible for dimerization whereas the basic region mediates sequence specific DNA binding. Human DEC, mouse STRA and rat SHARP proteins represent a new class of bHLH proteins. DEC/STRA/SHARP proteins show high similarities (∼40%) to Drosophila Hairy and E(spl) as well as the mammalian homologues (e.g., HES) in the bHLH domain. However, they lack the C-terminal WRPW motif which is present at all other Hairy/E(spl)/Hes proteins and mediates transcription repression. These structural differences distinguish DEC/STRA/SHARPs from other bHLH proteins and indicate that they have distinct biological functions. The purpose of this dissertation is to elucidate the oncogenic roles of DEC1 and determine the molecular actions of DEC1 on transcription regulation. ^ Expression measurments demonstrate that DEC1 is abundantly expressed in cancer tissues but not in adjacent normal tissues. In stable transfectants, DEC1 inhibits cell proliferation, antagonizes serum deprivation-induced apoptosis, and selectively decreases the activities of several major caspases. Western blotting analyses identify that antiapoptotic protein survivin is a functional mediator responsible for DEC1-directed antiapoptotic activity. DEC1 and survivin exhibit a paralleled expression pattern in paired tumor-normal tissues. In co-transfection experiments, DEC1 stimulates the survivin promoter, and this mechanism relies on the physical interactions with Sp1 sites in the proximal promoter. In contrast, DEC1 and its structurally related protein DEC2 show an inverted expression pattern in paired tumor-normal tissues. Forced expression of DEC1 causes proportional decreases in the expression of DEC2 in stable transfectants. Co-transfection with DEC1 represses the activity of a DEC2 promoter reporter by as much as 90%. The DEC1 mediated transcription repression is achieved by direct binding to the E-box element in the proximal promoter of DEC2. The established activation of the survivin promoter provides a molecular explanation for its oncogenic involvement, and the differential activities toward DEC2 and survivin promoters establish that DEC1 can act as a repressor or an activator depending on the genomic context of a target gene. ^
Health Sciences, Toxicology
"The DEC1 transcription factor: Oncogenic involvement and molecular mechanisms on transcription regulation"
Dissertations and Master's Theses (Campus Access).