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Molecular and Cellular Biology, July 2006, p. 5043-5054, Vol. 26, No. 13
0270-7306/06/$08.00+0     doi:10.1128/MCB.02387-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Gene 33/RALT Is Induced by Hypoxia in Cardiomyocytes, Where It Promotes Cell Death by Suppressing Phosphatidylinositol 3-Kinase and Extracellular Signal-Regulated Kinase Survival Signaling

Dazhong Xu,1 Richard D. Patten,1 Thomas Force,2 and John M. Kyriakis1*

Molecular Cardiology Research Institute, Tufts-New England Medical Center and Department of Medicine, Tufts University School of Medicine, 750 Washington Street, Boston, Massachusetts,1 Center for Translational Medicine, Thomas Jefferson University, 1025 Walnut Street, Philadelphia, Pennsylvania 191072

Received 14 December 2005/ Returned for modification 31 January 2006/ Accepted 17 April 2006

Ischemia in the heart deprives cardiomyocytes of oxygen, triggering cell death (myocardial infarction). Ischemia and its cell culture model, hypoxia, elicit a stress response program that contributes to cardiomyocyte death; however, the molecular components required to promote this process remain nebulous. Gene 33 is a 50-kDa cytosolic adapter protein that suppresses signaling from receptor Tyr kinases of the epidermal growth factor receptor/ErbB family. Here we show that adenoviral expression of Gene 33 swiftly stimulates cardiomyocyte death coincident with reduced Akt and extracellular signal-regulated kinase (ERK) signaling. Subjecting cardiomyocytes to hypoxia and then reoxygenation induces gene 33 mRNA and Gene 33 protein. RNA interference experiments indicate that endogenous Gene 33 reduces Akt and ERK signaling and is required for maximal hypoxia-induced cardiomyocyte death. Gene 33 levels are also strikingly increased in myocardial ischemic injury and infarction. Our results identify a new role for Gene 33 as a component in the molecular pathophysiology of ischemic injury.

* Corresponding author. Mailing address: Molecular Cardiology Research Institute, Tufts-New England Medical Center, 750 Washington Street, Box 8486, Boston, MA 02111. Phone: (617) 636-5190. Fax: (617) 636-5204. E-mail: jkyriakis{at}tufts-nemc.org.

Molecular and Cellular Biology, July 2006, p. 5043-5054, Vol. 26, No. 13
0270-7306/06/$08.00+0     doi:10.1128/MCB.02387-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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