PMID:17563398

Citation	Clavijo, C, Chen, JL, Kim, KJ, Reyland, ME and Ann, DK (2007) Protein kinase Cdelta-dependent and -independent signaling in genotoxic response to treatment of desferroxamine, a hypoxia-mimetic agent. Am. J. Physiol., Cell Physiol. 292:C2150-60
Abstract	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.
Links	PubMed Online version:10.1152/ajpcell.00425.2006
Keywords	Active Transport, Cell Nucleus/drug effects; Animals; Anoxia; Caspase 3/metabolism; Cell Line; DNA Damage; Deferoxamine/pharmacology; Epithelial Cells/cytology; Epithelial Cells/drug effects; Epithelial Cells/metabolism; Oncogene Protein v-akt/metabolism; Protein Kinase C-delta/metabolism; Rats; Signal Transduction
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
RAT:KPCD	involved_in	GO:0010243: response to organonitrogen compound	ECO:0000270: expression pattern evidence used in manual assertion		P		Seeded From UniProt	complete

References

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