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Regulation of heat-induced apoptosis by Mcl-1 degradation and its inhibition by Hsp70

A R Stankiewicz1, A M Livingstone, N Mohseni

  • 1Department of Molecular and Cellular Biology, University of Guelph, Guelph, Ontario, Canada.

Cell Death and Differentiation
|January 17, 2009
PubMed

Insights

Heat shock triggers cell death by degrading Mcl-1 protein, a key step in apoptosis. Heat shock protein 70 (Hsp70) prevents this degradation, preserving Mcl-1 and protecting cells from hyperthermia-induced damage.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Cellular stress initiates apoptosis via the intrinsic death pathway, regulated by Bcl-2 family proteins.
  • Mitochondrial release of apoptogenic factors like cytochrome c is crucial for apoptosis.
  • Hyperthermia activates proapoptotic Bax, but antiapoptotic proteins like Bcl-xL can inhibit this.

Purpose of the Study:

  • To investigate the heat-sensitive steps in hyperthermia-induced apoptosis.
  • To elucidate the role of Mcl-1 protein in cellular response to heat shock.
  • To determine the regulatory mechanism of Mcl-1 stability under heat stress.

Main Methods:

  • Utilized short hairpin RNA to deplete Noxa and assess its effect on Mcl-1 degradation.
  • Investigated the interaction between Noxa, Mcl-1, and the ubiquitin ligase Mule.
  • Examined the impact of Hsp70 overexpression on Mcl-1 levels and ubiquitination in heat-shocked cells.

Main Results:

  • Heat shock induces Mcl-1 protein loss, a critical step preceding apoptosis.
  • Noxa depletion protects cells from hyperthermia by preventing Mcl-1 degradation.
  • Heat shock causes Mcl-1 dissociation from Noxa, enabling Mule binding, ubiquitination, and degradation.
  • Hsp70 overexpression stabilizes Mcl-1 by reducing Mule interaction and enhancing Mcl-1 expression.

Conclusions:

  • Mcl-1 loss is a critical, heat-sensitive step in hyperthermia-induced apoptosis.
  • Hsp70 controls Mcl-1 stability, thereby regulating Bax activation and cell fate under heat stress.
  • This study reveals a novel regulatory pathway involving Mcl-1, Noxa, Mule, and Hsp70 in cellular thermotolerance.

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