Suppression of apoptosis in the protein kinase Cδ null mouse in vivo

Michael J. Humphries, Kirsten H. Limesand, Jonathan C. Schneider, Keiichi I. Nakayama, Steven M. Anderson, Mary E. Reyland

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Abstract

Protein kinase C (PKC) δ is an essential regulator of mitochondrial dependent apoptosis in epithelial cells. We have used the PKCδ -/- mouse to ask if loss of PKCδ protects salivary glands against γ-irradiation-induced apoptosis in vivo and to explore the mechanism underlying protection from apoptosis. We show that γ-irradiation in vivo results in a robust induction of apoptosis in the parotid glands of wild type mice, whereas apoptosis is suppressed by greater than 60% in the parotid glands of PKCδ-/- mice. Primary parotid cells from PKCδ-/- mice are defective in mitochondrial dependent apoptosis as indicated by suppression of etoposide-induced cytochrome c release, poly(ADP-ribose) polymerase cleavage, and caspase-3 activation. Notably, apoptotic responsiveness can be restored by re-introduction of PKCδ by adenoviral transduction. Etoposide and γ-irradiation-induced activation of p53 is similar in primary parotid cells and parotid glands from PKCδ+/+ and PKCδ-/- mice, indicating that PKCδ functions downstream of the DNA damage response. In contrast, activation of the c-Jun amino-terminal kinase is reduced in primary parotid cells from PKCδ-/- cells and in parotid C5 cells, which express a dominant inhibitory mutant of PKCδ. Similarly, c-Jun amino-terminal kinase activation is suppressed in vivo in γ-irradiated parotid glands from PKCδ-/- mice. These studies indicate an essential role for PKCδ downstream of the p53 response and upstream of the c-Jun amino-terminal kinase activation in DNA damage-induced apoptosis in vivo and in vitro.

Original languageEnglish
Pages (from-to)9728-9737
Number of pages10
JournalJournal of Biological Chemistry
Volume281
Issue number14
DOIs
Publication statusPublished - Apr 7 2006

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All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Humphries, M. J., Limesand, K. H., Schneider, J. C., Nakayama, K. I., Anderson, S. M., & Reyland, M. E. (2006). Suppression of apoptosis in the protein kinase Cδ null mouse in vivo. Journal of Biological Chemistry, 281(14), 9728-9737. https://doi.org/10.1074/jbc.M507851200