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Bcl-2 suppresses sarcoplasmic/endoplasmic reticulum Ca2+-ATPase expression in cystic fibrosis airways: role in oxidant-mediated cell death.

Publication ,  Journal Article
Ahmad, S; Ahmad, A; Dremina, ES; Sharov, VS; Guo, X; Jones, TN; Loader, JE; Tatreau, JR; Perraud, A-L; Schöneich, C; Randell, SH; White, CW
Published in: Am J Respir Crit Care Med
May 1, 2009

RATIONALE: Modulation of the activity of sarcoendoplasmic reticulum calcium ATPase (SERCA) can profoundly affect Ca(2+) homeostasis. Although altered calcium homeostasis is a characteristic of cystic fibrosis (CF), the role of SERCA is unknown. OBJECTIVES: This study provides a comprehensive investigation of expression and activity of SERCA in CF airway epithelium. A detailed study of the mechanisms underlying SERCA changes and its consequences was also undertaken. METHODS: Lung tissue samples (bronchus and bronchiole) from subjects with and without CF were evaluated by immunohistochemistry. Protein and mRNA expression in primary non-CF and CF cells was determined by Western and Northern blots. MEASUREMENTS AND MAIN RESULTS: SERCA2 expression was decreased in bronchial and bronchiolar epithelia of subjects with CF. SERCA2 expression in lysates of polarized tracheobronchial epithelial cells from subjects with CF was decreased by 67% as compared with those from subjects without CF. Several non-CF and CF airway epithelial cell lines were also probed. SERCA2 expression and activity were consistently decreased in CF cell lines. Adenoviral expression of mutant F508 cystic fibrosis transmembrane regulator gene (CFTR), inhibition of CFTR function pharmacologically (CFTR(inh)172), or stable expression of antisense oligonucleotides to inhibit CFTR expression caused decreased SERCA2 expression. In CF cells, SERCA2 interacted with Bcl-2, leading to its displacement from caveolae-related domains of endoplasmic reticulum membranes, as demonstrated in sucrose density gradient centrifugation and immunoprecipitation studies. Knockdown of SERCA2 using siRNA enhanced epithelial cell death due to ozone, hydrogen peroxide, and TNF-alpha. CONCLUSIONS: Reduced SERCA2 expression may alter calcium signaling and apoptosis in CF. These findings decrease the likelihood of therapeutic benefit of SERCA inhibition in CF.

Duke Scholars

Published In

Am J Respir Crit Care Med

DOI

EISSN

1535-4970

Publication Date

May 1, 2009

Volume

179

Issue

9

Start / End Page

816 / 826

Location

United States

Related Subject Headings

  • Sarcoplasmic Reticulum Calcium-Transporting ATPases
  • Respiratory System
  • Respiratory Mucosa
  • Proto-Oncogene Proteins c-bcl-2
  • Mutation
  • Immunohistochemistry
  • Humans
  • Epithelial Cells
  • Endoplasmic Reticulum
  • Cystic Fibrosis Transmembrane Conductance Regulator
 

Citation

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ICMJE
MLA
NLM
Ahmad, S., Ahmad, A., Dremina, E. S., Sharov, V. S., Guo, X., Jones, T. N., … White, C. W. (2009). Bcl-2 suppresses sarcoplasmic/endoplasmic reticulum Ca2+-ATPase expression in cystic fibrosis airways: role in oxidant-mediated cell death. Am J Respir Crit Care Med, 179(9), 816–826. https://doi.org/10.1164/rccm.200807-1104OC
Ahmad, Shama, Aftab Ahmad, Elena S. Dremina, Victor S. Sharov, Xiaoling Guo, Tara N. Jones, Joan E. Loader, et al. “Bcl-2 suppresses sarcoplasmic/endoplasmic reticulum Ca2+-ATPase expression in cystic fibrosis airways: role in oxidant-mediated cell death.Am J Respir Crit Care Med 179, no. 9 (May 1, 2009): 816–26. https://doi.org/10.1164/rccm.200807-1104OC.
Ahmad S, Ahmad A, Dremina ES, Sharov VS, Guo X, Jones TN, et al. Bcl-2 suppresses sarcoplasmic/endoplasmic reticulum Ca2+-ATPase expression in cystic fibrosis airways: role in oxidant-mediated cell death. Am J Respir Crit Care Med. 2009 May 1;179(9):816–26.
Ahmad, Shama, et al. “Bcl-2 suppresses sarcoplasmic/endoplasmic reticulum Ca2+-ATPase expression in cystic fibrosis airways: role in oxidant-mediated cell death.Am J Respir Crit Care Med, vol. 179, no. 9, May 2009, pp. 816–26. Pubmed, doi:10.1164/rccm.200807-1104OC.
Ahmad S, Ahmad A, Dremina ES, Sharov VS, Guo X, Jones TN, Loader JE, Tatreau JR, Perraud A-L, Schöneich C, Randell SH, White CW. Bcl-2 suppresses sarcoplasmic/endoplasmic reticulum Ca2+-ATPase expression in cystic fibrosis airways: role in oxidant-mediated cell death. Am J Respir Crit Care Med. 2009 May 1;179(9):816–826.

Published In

Am J Respir Crit Care Med

DOI

EISSN

1535-4970

Publication Date

May 1, 2009

Volume

179

Issue

9

Start / End Page

816 / 826

Location

United States

Related Subject Headings

  • Sarcoplasmic Reticulum Calcium-Transporting ATPases
  • Respiratory System
  • Respiratory Mucosa
  • Proto-Oncogene Proteins c-bcl-2
  • Mutation
  • Immunohistochemistry
  • Humans
  • Epithelial Cells
  • Endoplasmic Reticulum
  • Cystic Fibrosis Transmembrane Conductance Regulator