**7. Future perspective**

PKC plays a pivotal role in the control of apoptotic cell death in response to a diverse array of stress stimuli. Thus PKC is a pro-apoptotic kinase activated by multiple mechanisms, including subcellular translocation and proteolysis. The proteolytic activation of PKC is also important not only in activating the downstream apoptotic cascade including p53, but

Role for PKCδ on Apoptosis in the DNA Damage Response 299

understanding of how the PKC signaling pathway is influenced when cancer cells acquire resistance to chemotherapeutic drugs. Considering the importance of PKC in genotoxic stress-induced apoptosis, a thorough understanding of how it controls apoptosis should benefit cancer therapeutic potentials. Finally, novel PKC-based therapy may be used in combination with other agents to confer synergism and prevent the development for drug

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Brodie, C., Blumberg, P. M. (2003). Regulation of cell apoptosis by protein kinase c delta.

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Carpenter, L., Cordery, D., Biden, T. J. (2002). Inhibition of protein kinase C delta protects

Casabona, G. (1997). Intracellular signal modulation: a pivotal role for protein kinase C.

Chen, N., Ma, W., Huang, C., Dong, Z. (1999). Translocation of protein kinase Cepsilon

Chernov, M. V., Bean, L. J., Lerner, N., Stark, G. R. (2001). Regulation of ubiquitination and

Chernov, M. V., Ramana, C. V., Adler, V. V., Stark, G. R. (1998). Stabilization and activation

Clemens, M. J., Trayner, I., Menaya, J. (1992). The role of protein kinase C isoenzymes in the regulation of cell proliferation and differentiation. J Cell Sci 103 ( Pt 4):881-7. Datta, R., Kojima, H., Yoshida, K., Kufe, D. (1997). Caspase-3-mediated cleavage of protein

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also in amplifying upstream caspase signaling. Most of the studies mentioned above suggest that the role of PKC in the induction of apoptosis is tightly associated with its caspasedependent cleavage and the regulation of p53. However, functional regulation of p53 by PKC remains largely unclear. In this regard, thorough investigation coupled with PKC and p53 should be enhanced from multiple views. In the encounter with genotoxic insults, ATM controls various cellular responses, such as cell cycle arrest, transcription, DNA repair, and apoptosis. In this context, DNA damage-induced PKC is modulated under ATM, suggesting the notion that establishment of the ATMPKCp53 signaling cascade provides new mechanistic light on how PKC functions as the pro-apoptotic kinase in the nucleus (Figure 1) (Yoshida 2007a, Yoshida 2008a). While dysregulation of the PKC signalsome confers resistance to anticancer drugs (Meinhardt et al. 1999), there is little

Fig. 1. A hypothetical schema for nuclear targeting of PKC in response to DNA damage. Following DNA damage, PKC translocates from the cytoplasm into the nucleus. In addition, some genotoxic stress also exerts cytoplasmic oxidative stress to activate PKC. In the nucleus, PKC is activated by ATM, then induces apoptosis (or DNA repair) in a p53 dependent manner.

understanding of how the PKC signaling pathway is influenced when cancer cells acquire resistance to chemotherapeutic drugs. Considering the importance of PKC in genotoxic stress-induced apoptosis, a thorough understanding of how it controls apoptosis should benefit cancer therapeutic potentials. Finally, novel PKC-based therapy may be used in combination with other agents to confer synergism and prevent the development for drug resistance.
