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Article Addendum

PERK-dependent regulation of HSP70 expression and the regulation of autophagy

Margaret A. Park, David T. Curiel, Costas Koumenis, Martin Graf, Ching-Shih Chen, Paul B. Fisher, Steven Grant and Paul Dent

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The manuscript by Park et al. (Mol. Pharm. (2008) mol.107.042697 / PMID: 18182481) further defines the mechanism(s) by which OSU-03012 (OSU) kills transformed cells. It notes that in PKR-like endoplasmic reticulum kinase null cells (PERK^-/-) the lethality of OSU is attenuated. OSU enhances the expression of ATG5 in a PERK-dependent fashion and promotes the ATG5-dependent formation of vesicles containing LC3, followed by a subsequent cleavage of cathepsin B and a cathepsin B-dependent formation of low pH intracellular vesicles; cathepsin B is activated and released into the cytosol, and genetic suppression of cathepsin B or AIF function significantly suppresses cell killing. In parallel, OSU causes PERK-dependent increases in HSP70 expression and decreases in HSP90 and Grp78/BiP expression. Inhibition of HSP70 expression enhances OSU toxicity and over-expression of HSP70 suppresses OSU-induced low pH vesicle formation and lethality. Thus, in this system PERK signaling promotes autophagy, which is causally linked to lysosomal dysfunction, cathepsin activation and cell death. However, in parallel, PERK signaling acts to suppress autophagy and lysosomal dysfunction by increasing the expression of HSP70. These findings may help explain why, in a cell type and stimulus-dependent fashion; autophagy has been noted to act either as a protective or as a toxic signal in cells.

Addendum to: Park M, Yacoub A, Rahmani M, Zhang G, Hart L, Hagan M, Calderwood S, Sherman M, Koumenis C, Spiegel S, Chen CS, Graf M, Curiel D, Fisher P, Grant S, Dent P. OSU-03012 stimulates PERK-dependent increases in HSP70 expression, attenuating its lethal actions in transformed cells. Mol Pharmacol 2008; Epub ahead of print.

Authors

Margaret A. Park

Department of Biochemistry; Virginia Commonwealth University; Richmond, Virginia USA

David T. Curiel

University of Alabama at Birmingham

Costas Koumenis

University of Pennsylvania

Martin Graf

Virginia Commonwealth University

Ching-Shih Chen

ohio state university

Paul B. Fisher

Department of Human Genetics; Institute for Molecular Medicine; Virginia Commonwealth University; Richmond, Virginia USA

Steven Grant

Departments of Biochemistry and Medicine; Institute for Molecular Medicine; Virginia Commonwealth University; Richmond, Virginia USA

Paul Dent

Departments of Biochemistryand Immunology; Institute for Molecular Medicine; Virginia Commonwealth University; Richmond, Virginia USA

Purchase article for $19

Subscribe to this journal for $99/year