Published online before print December 30, 2008

This Article Full Text Full Text (PDF) All Versions of this Article: ajpath.2009.080180v1 174/2/449    most recent Purchase Article View Shopping Cart Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Buder-Hoffmann, S. A. Articles by Mossman, B. T. Search for Related Content PubMed PubMed Citation Articles by Buder-Hoffmann, S. A. Articles by Mossman, B. T.

(American Journal of Pathology. 2009;174:449-459.)
© 2009 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2009.080180

A Protein Kinase C-Dependent Protein Kinase D Pathway Modulates ERK1/2 and JNK1/2 Phosphorylation and Bim-Associated Apoptosis by Asbestos

Sylke A. Buder-Hoffmann^*, Arti Shukla^*, Trisha F. Barrett^*, Maximilian B. MacPherson^*, Karen M. Lounsbury and Brooke T. Mossman^*

From the Departments of Pathology^* and Pharmacology, University of Vermont College of Medicine, Burlington, Vermont

Inhalation of asbestos and oxidant-generating pollutants causes injury and compensatory proliferation of lung epithelium, but the signaling mechanisms that lead to these responses are unclear. We hypothesized that a protein kinase (PK)C-dependent PKD pathway was able to regulate downstream mitogen-activated protein kinases, affecting pro- and anti-apoptotic responses to asbestos. Elevated levels of phosphorylated PKD (p-PKD) were observed in distal bronchiolar epithelial cells of mice inhaling asbestos. In contrast, PKC–/– mice showed significantly lower levels of p-PKD in lung homogenates and in situ after asbestos inhalation. In a murine lung epithelial cell line, asbestos caused significant increases in the phosphorylation of PKC-dependent PKD, ERK1/2, and JNK1/2/c-Jun that occurred with decreases in the BH3-only pro-apoptotic protein, Bim. Silencing of PKC, PKD, and use of small molecule inhibitors linked the ERK1/2 pathway to the prevention of Bim-associated apoptosis as well as the JNK1/2/c-Jun pathway to the induction of apoptosis. Our studies are the first to show that asbestos induces PKD phosphorylation in lung epithelial cells both in vivo and in vitro. PKC-dependent PKD phosphorylation by asbestos is causally linked to a cellular pathway that involves the phosphorylation of both ERK1/2 and JNK1/2, which play opposing roles in the apoptotic response induced by asbestos.

This article has been cited by other articles:

				N. H. Heintz, Y. M. W. Janssen-Heininger, and B. T. Mossman Asbestos, Lung Cancers, and Mesotheliomas: From Molecular Approaches to Targeting Tumor Survival Pathways Am. J. Respir. Cell Mol. Biol., February 1, 2010; 42(2): 133 - 139. [Abstract] [Full Text] [PDF]