Alterations in protein kinase C activity and processing during zinc-deficiency-induced cell death

Susan S. Chou, Michael S. Clegg, Tony Y. Momma, Brad J. Niles, Jodie Y. Duffy, George P. Daston, Carl L Keen

Research output: Contribution to journalArticle

28 Scopus citations

Abstract

Protein kinases C (PKCs) are a family of serine/threonine kinases that are critical for signal transduction pathways involved in growth, differentiation and cell death. All PKC isoforms have four conserved domains, C1-C4. The C1 domain contains cysteine-rich finger-like motifs, which bind two zinc atoms. The zinc-finger motifs modulate diacylglycerol binding; thus, intracellular zinc concentrations could influence the activity and localization of PKC family members. 3T3 cells were cultured in zinc-deficient or zinc-supplemented medium for up to 32 h. Cells cultured in zinc-deficient medium had decreased zinc content, lowered cytosolic classical PKC activity, increased caspase-3 processing and activity, and reduced cell number. Zinc-deficient cytosols had decreased activity and expression levels of PKC-α, whereas PKC-α phosphorylation was not altered. Inhibition of PKC-α with Gö6976 had no effect on cell number in the zinc-deficient group. Proteolysis of the novel PKC family member, PKC-δ, to its 40-kDa catalytic fragment occurred in cells cultured in the zinc-deficient medium. Occurrence of the PKC-δ fragment in mitochondria was co-incident with caspase-3 activation. Addition of the PKC-δ inhibitor, rottlerin, or zinc to deficient medium reduced or eliminated proteolysis of PKC-δ, activated caspase-3 and restored cell number. Inhibition of caspase-3 processing by Z-DQMD-FMK (Z-Asp-Gln-Met-Asp- fluoromethylketone) did not restore cell number in the zinc-deficient group, but resulted in processing of full-length PKC-δ to a 56-kDa fragment. These results support the concept that intracellular zinc concentrations influence PKC activity and processing, and that zinc-deficiency-induced apoptosis occurs in part through PKC-dependent pathways.

Original languageEnglish (US)
Pages (from-to)63-71
Number of pages9
JournalBiochemical Journal
Volume383
Issue number1
DOIs
StatePublished - Oct 1 2004

    Fingerprint

Keywords

  • 3T3 cell
  • Apoptosis
  • Caspase-3
  • Protein kinase C-α
  • Protein kinase C-δ
  • Zinc

ASJC Scopus subject areas

  • Biochemistry

Cite this

Chou, S. S., Clegg, M. S., Momma, T. Y., Niles, B. J., Duffy, J. Y., Daston, G. P., & Keen, C. L. (2004). Alterations in protein kinase C activity and processing during zinc-deficiency-induced cell death. Biochemical Journal, 383(1), 63-71. https://doi.org/10.1042/BJ20040074