AJP - Lung AJP: Advances in Physiology Education
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH
QUICK SEARCH:   [advanced]


     

Am J Physiol Lung Cell Mol Physiol (June 22, 2007). doi:10.1152/ajplung.00025.2007
This Article
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
293/3/L720    most recent
00025.2007v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Mulugeta, S.
Right arrow Articles by Beers, M. F
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Mulugeta, S.
Right arrow Articles by Beers, M. F
Submitted on January 18, 2007
Accepted on June 19, 2007

Misfolded BRICHOS SP-C mutant proteins induce apoptosis via caspase 4 and cytochrome c related mechanisms

Surafel Mulugeta1*, Jean Ann Maguire1, Jennifer L Newitt1, Scott J Russo1, Adam Kotorashvili1, and Michael F Beers1

1 Medicine, Pulmonary and Critical Care Division, University of Pennsylvania, Philadelphia, Pennsylvania, United States

* To whom correspondence should be addressed. E-mail: mulugeta{at}mail.med.upenn.edu.

Several mutations within the BRICHOS domain of Surfactant Protein C (SP-C) have been linked to interstitial lung disease. Recent studies have suggested that these mutations cause misfolding of the proprotein (proSP-C), which initiates the unfolded protein response in order to resolve improper folding or promote protein degradation. We have reported that in vitro expression of one of these proteins, the exon 4 deletion mutant (hSP-C{Delta}exon4), causes ER stress, inhibits proteasome function, and activates caspase 3 mediated apoptosis. To further elucidate mechanisms and common pathways for cellular dysfunction, various assays were performed by transiently expressing two SP-C BRICHOS domain mutant (BRISPC) proteins (hSP-C{Delta}exon4, hSP-CL188Q) and control proteins in lung epithelia-derived A549 and kidney epithelia-derived (HEK293) GFPu-1 cell lines. Compared to controls, cells expressing either BRICHOS mutant protein consistently exhibited increased formation of insoluble aggregates, enhanced promotion of inositol-requiring enzyme 1 (IRE1)-dependent splicing of X-box binding protein-1 (XBP-1), significant inhibition of proteasome activity, enhanced induction of mitochondrial cytochrome c release, and increased activations of caspase 4 and caspase 3 leading to apoptosis. These results suggest common cellular responses, including initiation of cell-death signaling pathways, to these lung disease-associated BRISPC proteins.




This article has been cited by other articles:


Home page
 ERRHome page
P. W. Noble
Epithelial fibroblast triggering and interactions in pulmonary fibrosis
Eur. Respir. Rev., December 1, 2008; 17(109): 123 - 129.
[Abstract] [Full Text] [PDF]

Home page
 ERRHome page
J. E. Loyd
Gene expression profiling: can we identify the right target genes?
Eur. Respir. Rev., December 1, 2008; 17(109): 163 - 167.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
W. E. Lawson, P. F. Crossno, V. V. Polosukhin, J. Roldan, D.-S. Cheng, K. B. Lane, T. R. Blackwell, C. Xu, C. Markin, L. B. Ware, et al.
Endoplasmic reticulum stress in alveolar epithelial cells is prominent in IPF: association with altered surfactant protein processing and herpesvirus infection
Am J Physiol Lung Cell Mol Physiol, June 1, 2008; 294(6): L1119 - L1126.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Biol. CellHome page
M. Dong, J. P. Bridges, K. Apsley, Y. Xu, and T. E. Weaver
ERdj4 and ERdj5 Are Required for Endoplasmic Reticulum-associated Protein Degradation of Misfolded Surfactant Protein C
Mol. Biol. Cell, June 1, 2008; 19(6): 2620 - 2630.
[Abstract] [Full Text] [PDF]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH
Visit Other APS Journals Online
Copyright © 2007 by the American Physiological Society.