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Protein kinase Cdelta-dependent and -independent signaling in genotoxic response to treatment of desferroxamine, a hypoxia-mimetic agent.

Authors: Clavijo, C  Chen, JL  Kim, KJ  Reyland, ME  Ann, DK 
Citation: Clavijo C, etal., Am J Physiol Cell Physiol. 2007 Jun;292(6):C2150-60.
Pubmed: (View Article at PubMed) PMID:17563398
DOI: Full-text: DOI:10.1152/ajpcell.00425.2006

Protein kinase C (PKC) plays a critical role in diseases such as cancer, stroke, and cardiac ischemia and participates in a variety of signal transduction pathways including apoptosis, cell proliferation, and tumor suppression. Here, we demonstrate that PKCdelta is proteolytically cleaved and translocated to the nucleus in a time-dependent manner on treatment of desferroxamine (DFO), a hypoxia-mimetic agent. Specific knockdown of the endogenous PKCdelta by RNAi (sh-PKCdelta) or expression of the kinase-dead (Lys376Arg) mutant of PKCdelta (PKCdeltaKD) conferred modulation on the cellular adaptive responses to DFO treatment. Notably, the time-dependent accumulation of DFO-induced phosphorylation of Ser-139-H2AX (gamma-H2AX), a hallmark for DNA damage, was altered by sh-PKCdelta, and sh-PKCdelta completely abrogated the activation of caspase-3 in DFO-treated cells. Expression of Lys376Arg-mutated PKCdelta-enhanced green fluorescent protein (EGFP) appears to abrogate DFO/hypoxia-induced activation of endogenous PKCdelta and caspase-3, suggesting that PKCdeltaKD-EGFP serves a dominant-negative function. Additionally, DFO treatment also led to the activation of Chk1, p53, and Akt, where DFO-induced activation of p53, Chk1, and Akt occurred in both PKCdelta-dependent and -independent manners. In summary, these findings suggest that the activation of a PKCdelta-mediated signaling network is one of the critical contributing factors involved in fine-tuning of the DNA damage response to DFO treatment.


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CRRD Object Information
CRRD ID: 1642537
Created: 2007-09-28
Species: All species
Last Modified: 2007-09-28
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.