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Atypical protein kinase C zeta exhibits a proapoptotic function in ovarian cancer

Abstract:

Intracellular signaling governed by serine/threonine kinases comprises the molecular interface between cell surface receptors and the nuclear transcriptional machinery. The protein kinase C (PKC) family members are involved in the control of many signaling processes directing cell proliferation, motility, and survival. Here, we examined a role of different PKC isoenzymes in protein phosphatase 2A (PP2A) and HRSL3 tumor suppressor-dependent cell death induction in the ovarian carcinoma cell line OVCAR-3. Phosphorylation and activity of PKC isoenzymes were measured in response to PP2A or phosphoinositide 3-kinase inhibition or HRSL3 overexpression. These experiments indicated a regulation of PKC, epsilon, zeta, and iota through PP2A and/or HRSL3, but not of PKCalpha and beta. Using isoform-specific peptide inhibitors and overexpression approaches, we verified a contribution to PP2A- and HRLS3-dependent apoptosis only for PKCzeta, suggesting a proapoptotic function of this kinase. We observed a significant proportion of human ovarian carcinomas expressing high levels of PKCzeta, which correlated with poor prognosis. Primary ovarian carcinoma cells isolated from patients also responded to okadaic acid treatment with increased phosphorylation of PKCzeta and apoptosis induction. Thus, our data indicate a contribution of PKCzeta in survival control in ovarian carcinoma cells and suggest that upregulation or activation of tyrosine kinase receptors in this tumor might impinge onto apoptosis control through the negative regulation of the atypical PKCzeta.

20501645

Projects: A2.3: Cross-talk and distinct properties of growth factor signalling reg..., B2.1: Hepatic stellate cells as source and target for hepatocellular gro...

Mol. Cancer Res.
Mol. Cancer Res. 8(6): 919-34
25th May 2010

Irina Nazarenko, Marcel Jenny, Jana Keil, Cornelia Gieseler, Karen Weisshaupt, Jalid Sehouli, Stefan Legewie, Lena Herbst, Wilko Weichert, Silvia Darb-Esfahani, Manfred Dietel, Reinhold Schäfer, Florian Ueberall, Christine Sers

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[Stefan Legewie]

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Cell
Views: 2220
  • Created: 11th Sep 2012 at 11:39
  • Last updated: 24th Oct 2013 at 16:20

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