| First Author | Buder-Hoffmann SA | Year | 2009 |
| Journal | Am J Pathol | Volume | 174 |
| Issue | 2 | Pages | 449-59 |
| PubMed ID | 19116364 | Mgi Jnum | J:144200 |
| Mgi Id | MGI:3830420 | Doi | 10.2353/ajpath.2009.080180 |
| Citation | Buder-Hoffmann SA, et al. (2009) A protein kinase Cdelta-dependent protein kinase D pathway modulates ERK1/2 and JNK1/2 phosphorylation and Bim-associated apoptosis by asbestos. Am J Pathol 174(2):449-59 |
| abstractText | 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)Cdelta-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, PKCdelta-/- 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 PKCdelta-dependent PKD, ERK1/2, and JNK1/2/c-Jun that occurred with decreases in the BH3-only pro-apoptotic protein, Bim. Silencing of PKCdelta, 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. PKCdelta-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. |
