Modulation of tolerance by mutant heat shock transcription factors

AUTOR(ES)

Xia, Wenle

FONTE

Cell Stress Society International

RESUMO

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 (Hsfl), which factor may therefore represent a preferred target for therapeutic modulation of tolerance. In support, positively acting (Hsfl(+)) and negatively acting (Hsfl(−)) mutants of Hsfl were identified. Inhibition of endogenous Hsfl activity by Hsfl(−) prevents stress-induced Hsp synthesis and development of tolerance. Hsfl(+) 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 Hsfl 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 Hsfl a preferred target for pharmacological intervention to deliberately induce tolerance.

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