Protein kinase C alpha and zeta differentially regulate death-inducing signaling complex formation in cigarette smoke extract-induced apoptosis

Jeong-Woong Park; Hong Pyo Kim; Seon-Jin Lee; Xue Wang; Yong Wang; Emeka Ifedigbo; Simon C Watkins; Motoi Ohba; Stefan W Ryter; Yatin M Vyas; Augustine M K Choi

doi:10.4049/jimmunol.180.7.4668

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Protein kinase C alpha and zeta differentially regulate death-inducing signaling complex formation in cigarette smoke extract-induced apoptosis

Journal article

Peer reviewed

Protein kinase C alpha and zeta differentially regulate death-inducing signaling complex formation in cigarette smoke extract-induced apoptosis

Jeong-Woong Park, Hong Pyo Kim, Seon-Jin Lee, Xue Wang, Yong Wang, Emeka Ifedigbo, Simon C Watkins, Motoi Ohba, Stefan W Ryter, Yatin M Vyas, …

The Journal of immunology (1950), Vol.180(7), pp.4668-4678

04/01/2008

DOI: 10.4049/jimmunol.180.7.4668

PMID: 18354190

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Abstract

Cigarette smoke, a major risk factor in emphysema, causes cell death by incompletely understood mechanisms. Death-inducing signaling complex (DISC) formation is an initial event in Fas-mediated apoptosis. We demonstrate that cigarette smoke extract (CSE) induces DISC formation in human lung fibroblasts (MRC-5) and promotes DISC trafficking from the Golgi complex to membrane lipid rafts. We demonstrate a novel role of protein kinase C (PKC) in the regulation of DISC formation and trafficking. The PKC isoforms, PKCalpha, zeta, epsilon, and eta, were activated by CSE exposure. Overexpression of wild-type PKCalpha inhibited, while PKCzeta promoted, CSE-induced cell death. Dominant-negative (dn)PKCzeta protected against CSE-induced cell death by suppressing DISC formation and caspase-3 activation, while dnPKCalpha enhanced cell death by promoting these events. DISC formation was augmented by wortmannin, an inhibitor of PI3K. CSE-induced Akt phosphorylation was reduced by dnPKCalpha, but it was increased by dnPKCzeta. Expression of PKCalpha in vivo inhibited DISC formation, caspase-3/8 activation, lung injury, and cell death after prolonged cigarette smoke exposure, whereas expression of PKCzeta promoted caspase-3 activation. In conclusion, CSE-induced DISC formation is differentially regulated by PKCalpha and PKCzeta via the PI3K/Akt pathway. These results suggest that modulation of PKC may have therapeutic potential in the prevention of smoke-related lung injury.

Cell Line

Protein Kinase C-alpha - metabolism

Apoptosis - drug effects

Humans

Mice, Inbred C57BL

Male

Enzyme Activation - drug effects

Phosphoserine - metabolism

Protein Transport

Animals

Caspases - metabolism

Protein Kinase C - metabolism

Tobacco - chemistry

Tobacco Smoke Pollution

Mice

Proto-Oncogene Proteins c-akt - metabolism

Death Domain Receptor Signaling Adaptor Proteins - metabolism

Details

Title: Subtitle: Protein kinase C alpha and zeta differentially regulate death-inducing signaling complex formation in cigarette smoke extract-induced apoptosis
Creators: Jeong-Woong Park - Department of Pulmonary and Critical Care Medicine, Gachon Medical School, Gil Medical Center, Inchon, Republic of Korea
Hong Pyo Kim
Seon-Jin Lee
Xue Wang
Yong Wang
Emeka Ifedigbo
Simon C Watkins
Motoi Ohba
Stefan W Ryter
Yatin M Vyas
Augustine M K Choi
Resource Type: Journal article
Publication Details: The Journal of immunology (1950), Vol.180(7), pp.4668-4678
DOI: 10.4049/jimmunol.180.7.4668
PMID: 18354190
ISSN: 0022-1767
eISSN: 1550-6606
Grant note: P01 HL 70807 / NHLBI NIH HHS R01 HL 60234 / NHLBI NIH HHS K08 AI051402 / NIAID NIH HHS K08 AI 51402 / NIAID NIH HHS R01 HL 55330 / NHLBI NIH HHS R01 HL 079904 / NHLBI NIH HHS
Language: English
Date published: 04/01/2008
Academic Unit: Stead Family Department of Pediatrics
Record Identifier: 9984093310502771

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