Protein kinase Cdelta-dependent and -independent signaling in genotoxic response to treatment of desferroxamine, a hypoxia-mimetic agent |
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Authors: | Clavijo Carlos Chen Jo-Lin Kim Kwang-Jin Reyland Mary E Ann David K |
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Institution: | Department of Molecular Pharmacology, University of Southern California, Los Angeles, USA. |
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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 PKC 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 PKC by RNAi (sh-PKC ) or expression of the kinase-dead (Lys376Arg) mutant of PKC (PKC KD) conferred modulation on the cellular adaptive responses to DFO treatment. Notably, the time-dependent accumulation of DFO-induced phosphorylation of Ser-139-H2AX ( -H2AX), a hallmark for DNA damage, was altered by sh-PKC , and sh-PKC completely abrogated the activation of caspase-3 in DFO-treated cells. Expression of Lys376Arg-mutated PKC -enhanced green fluorescent protein (EGFP) appears to abrogate DFO/hypoxia-induced activation of endogenous PKC and caspase-3, suggesting that PKC KD-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 PKC -dependent and -independent manners. In summary, these findings suggest that the activation of a PKC -mediated signaling network is one of the critical contributing factors involved in fine-tuning of the DNA damage response to DFO treatment. DNA damage; caspase-3; Akt |
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