Modulation of tolerance by mutant heat shock transcription factors.
It ought to be possible to recruit normal cellular defenses to mitigate ischemia/reperfusion damage and to reduce toxicity of chemotherapeutic drugs. Stress-preconditioned cells acquire a tolerant state characterized by increased resistance to such insults. This state is widely believed to be mediated, partially, by heat shock proteins (Hsps). Indirect evidence suggests that stress-induced Hsp expression is controlled by heat shock transcription factor 1 (Hsf1), which factor may therefore represent a preferred target for therapeutic modulation of tolerance. In support, positively acting (Hsf1(+)) and negatively acting (Hsf1(-)) mutants of Hsf1 were identified. Inhibition of endogenous Hsf1 activity by Hsf1(-) prevents stress-induced Hsp synthesis and development of tolerance. Hsf1(+) drastically enhances expression of major Hsps in the absence of stress and induces tolerance against heat, simulated ischemia and toxicity by cyclophosphamide. Where compared, tolerance induced was slightly better than that produced by heat preconditioning. Thus, development of the tolerant state is dependent on increased levels of the cohort of Hsps induced by stress preconditioning, and Hsf1 can induce accumulation of a typical set of Hsps, which proteins are alone capable of providing tolerance at a similar level as heat preconditioning. These findings make Hsf1 a preferred target for pharmacological intervention to deliberately induce tolerance.
Xia
W
W
Department of Biochemistry & Molecular Biology, University of Miami School of Medicine, Miami, FL, 33136, USA.
Vilaboa
N
N
Martin
J L
JL
Mestril
R
R
Guo
Y
Y
Voellmy
R
R
D002455:Cell Division; D002470:Cell Survival; D015500:Chloramphenicol O-Acetyltransferase / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006367:HeLa Cells; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins / Q000235:genetics* / Q000378:metabolism*; D006358:Hot Temperature; D006801:Humans; D008164:Luminescent Proteins / Q000235:genetics; D009154:Mutation; D011401:Promoter Regions, Genetic; D014176:Protein Biosynthesis; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D014162:Transfection
D004268:DNA-Binding Proteins; C000619706:HSF1 protein, human; D018840:HSP70 Heat-Shock Proteins; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins; D008164:Luminescent Proteins; D014157:Transcription Factors; D049452:Green Fluorescent Proteins; D015500:Chloramphenicol O-Acetyltransferase