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

Overview

MeSH

  • Animals
  • Caspases
  • Cell Line
  • Enzyme Activation
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Phosphoserine
  • Protein Transport
  • Proto-Oncogene Proteins c-akt

MeSH Major

  • Apoptosis
  • Death Domain Receptor Signaling Adaptor Proteins
  • Protein Kinase C
  • Protein Kinase C-alpha
  • Tobacco
  • Tobacco Smoke Pollution

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.

publication date

  • April 1, 2008

has subject area

  • Animals
  • Apoptosis
  • Caspases
  • Cell Line
  • Death Domain Receptor Signaling Adaptor Proteins
  • Enzyme Activation
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Phosphoserine
  • Protein Kinase C
  • Protein Kinase C-alpha
  • Protein Transport
  • Proto-Oncogene Proteins c-akt
  • Tobacco
  • Tobacco Smoke Pollution

Research

keywords

  • Journal Article

Identity

Language

  • eng

PubMed ID

  • 18354190

Additional Document Info

start page

  • 4668

end page

  • 4678

volume

  • 180

number

  • 7