PKC delta signaling: a dual role in regulating hypoxic stress-induced autophagy and apoptosis

Autophagy. 2009 Feb;5(2):244-6. doi: 10.4161/auto.5.2.7549. Epub 2009 Feb 5.

Abstract

The protein kinase C (PKC) family of serine/threonine kinases regulates diverse cellular function, including cell death, proliferation and survival. In particular, PKC delta governs the cellular homeostatic response against hypoxic stress. Autophagy, a lysosome-dependent degradative pathway, and apoptosis are two fundamental cellular pathways that respond to stress conditions, such as hypoxia, oxidative stress and nutrient starvation. Recently, we uncovered a novel role for PKC delta in the early stage of hypoxic response where PKC delta activates autophagy by promoting JNK1-mediated Bcl-2 phosphorylation and dissociation of the Bcl-2/Beclin 1 complex. Whereas acute hypoxic stress promotes autophagy, we have previously reported that prolonged hypoxic stress caused the cleavage of PKC delta by caspase-3, resulting in the nuclear translocation of a constitutively active catalytic fragment of PKC delta, PKC delta-CF. Moreover, PKC delta-CF also serves a feed-forward function for the reciprocal PKC delta and caspase-3 proteolytic activation. Here, we discussed the requirement for PKC delta and JNK1 for hypoxia-induced autophagy, and the kinetic relationship among Bcl-2/Beclin 1 interaction, caspase-3 activation and the steady-state level of Beclin 1 during hypoxic exposure. Based on these results, we propose a model for understanding the PKC delta-dependent crosstalk mechanisms between autophagy and apoptosis, both induced by hypoxic stress. These findings collectively support a pivotal role for PKC delta in regulating hypoxic stress with hitherto unappreciated significance.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Apoptosis Regulatory Proteins
  • Apoptosis*
  • Autophagy*
  • Beclin-1
  • Cell Hypoxia
  • Enzyme Activation
  • Humans
  • Mice
  • Mitogen-Activated Protein Kinase 8 / metabolism
  • Protein Kinase C-delta / metabolism*
  • Proteins / metabolism
  • Signal Transduction*
  • Stress, Physiological*

Substances

  • Apoptosis Regulatory Proteins
  • Beclin-1
  • Becn1 protein, mouse
  • Proteins
  • Protein Kinase C-delta
  • Mitogen-Activated Protein Kinase 8