Title

DAXX stimulates the cellular stress protein response by activating the transactivation competence of heat shock transcription factor HSF1

Date of Award

2002

Availability

Article

Degree Name

Doctor of Philosophy (Ph.D.)

First Committee Member

Richard W. Voellmy, Committee Chair

Abstract

HSF1 is the essential transcription factor that is required for the stress-induced expression of a heterogeneous class of proteins known as heat shock proteins (HSPs). Monomeric HSF1 is released from a HSP90-containing chaperone complex when the folding aides (chaperones) are needed to prevent intracellular aggregation of un- or missfolded proteins. Unbound HSF1 monomers form a homo-trimeric complex that accumulates in the nucleus and acquires the ability to bind to specific DNA sequences known as heat shock elements (HSEs) in promoters of genes that encode heat shock proteins.DAXX, a protein initially characterized as an enhancer of Fas-induced apoptosis, binds to the trimeric HSF1 complex---thereby stimulating the transcriptional competence of HSF1. This activation of trimeric HSF1 can be achieved in the absence of stress by overexpression of DAXX. DAXX fragments exert a dominant-negative effect on HSF1 activation by different types of stress. Interference with the expression of the DAXX protein by antisense oligonucleotides against the DAXX mRNA significantly interferes with the heat-induced HSF1 activity. The complete loss of daxx results in a defective stress protein response. These findings identify DAXX as the key mediator of activation of HSF1 transcriptional competence.The latter activation event appears to be associated with nuclear domain ND10 (PML oncogenic domain), which is known to be involved in a variety of cellular activities like aging, apoptosis, the cell cycle, stress response, hormone signaling, transcriptional regulation and development.Of the two kinases that are known to bind to DAXX only FIST/HIPK3 but not ASK1/MEKK5 co-mediates the activation of HSF1 by DAXX. The target of the protein kinase FIST is probably neither HSF1 nor DAXX but acts downstream of these two proteins.

Keywords

Biology, Molecular

Link to Full Text

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