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Peptide-mediated activation of Akt and extracellular regulated kinase signaling prevents lymphocyte apoptosis

Jonathan E. McDunn^*,,1, Jared T. Muenzer, Latif Rachdi, Katherine C. Chang^*, Chris G. Davis^*, W. Michael Dunne^||, David Piwnica-Worms^¶,#, Ernesto Bernal-Mizrachi and Richard S. Hotchkiss^*,,,¶

Department of
^* Anesthesiology,

Department of Surgery,

Department of Pediatrics,

Department of Medicine,

^|| Department of Molecular Microbiology,

^¶ Department of Molecular Biology and Pharmacology, and

^# Molecular Imaging Center, Mallinckrodt Institute of Radiology, Washington University School of Medicine, Saint Louis, Missouri, USA

¹Correspondence: Campus Box 8054, 660 South Euclid Ave., Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO, 63110, USA. E-mail: mcdunnj{at}wustl.edu

Lymphocyte apoptosis is a hallmark of sepsis and contributes to disease mortality. In other acute injuries, such as myocardial and cerebral ischemia/reperfusion, apoptosis plays a significant role in disease-associated morbidity and mortality. We previously showed that constitutive activation of the potent antiapoptotic Akt/protein kinase B signaling pathway in lymphocytes both reduces sepsis-induced lymphocyte apoptosis and confers a significant survival advantage compared to wild-type littermates. Here, we demonstrate a therapeutic approach to acutely augment Akt activity in a wild-type animal. A cell-permeable peptide conjugated to the Akt-binding domain of the endogenous Akt coactivator, Tcl-1, prolongs Akt activity, activates extracellular regulated kinase (ERK) signaling and protects lymphocytes from numerous apoptotic stimuli both in vitro and in vivo. Molecular approaches to activate the antiapoptotic Akt and ERK signaling pathways may provide a novel tool to study these signaling pathways, as well as a new antiapoptotic strategy for the treatment of sepsis and other acute injuries. McDunn, J. E., Muenzer, J. T., Rachdi, L., Chang, K. C., Davis, C. G., Dunne, W. M., Piwnica-Worms, D., Mizrachi, E.-B., Hotchkiss, R. S. Peptide-mediated activation of Akt and ERK signaling prevents lymphocyte apoptosis.

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