Co-Investigator: Mitchell P. Fink MD
Funding: NIH K08GM076344 (Project period: 7/3/06 to 6/30/11)
Poly (ADP-ribose) polymerase-1 (PARP-1) is a highly conserved multifunctional enzyme, and its catalytic activity is stimulated by DNA breaks. The activation of PARP-1 and subsequent depletion of nicotinamide adenine dinucleotide (NAD+) and adenosine triphosphate (ATP) contributes to significant cytotoxicity in inflammation of various etiologies. On the contrary, induction of heat shock response and production of heat shock protein 70 (HSP-70) is a cytoprotective defense mechanism in inflammation. Recent data suggests that PARP-1 modulates the expression of a number of cellular proteins at the transcriptional level. We hypothesized that the heat shock response is negatively modulated by PARP-1 activation. Our experiments indicate that PARP-1 modulates the heat shock response by functioning as a repressing factor of HSP-70 gene expression. We demonstrated that knockdown of PARP-1 gene increased HSP-70 gene expression as evidenced by increased DNA-binding activity of HSF-1, HSP-70 mRNA and protein expression. Secondly, using co-immunoprecipitation we demonstrated that PARP-1 may also regulate HSF-1 activation through direct interaction with this transcription factor.