Protein kinase C signaling and oxidative stress.
Oxidative stress is involved in the pathogenesis of various degenerative diseases including cancer. It is now recognized that low levels of oxidants can modify cell-signaling proteins and that these modifications have functional consequences. Identifying the target proteins for redox modification is key to understanding how oxidants mediate pathological processes such as tumor promotion. These proteins are also likely to be important targets for chemopreventive antioxidants, which are known to block signaling induced by oxidants and to induce their own actions. Various antioxidant preventive agents also inhibit PKC-dependent cellular responses. Therefore, PKC is a logical candidate for redox modification by oxidants and antioxidants that may in part determine their cancer-promoting and anticancer activities, respectively. PKCs contain unique structural features that are susceptible to oxidative modification. The N-terminal regulatory domain contains zinc-binding, cysteine-rich motifs that are readily oxidized by peroxide. When oxidized, the autoinhibitory function of the regulatory domain is compromised and, consequently, cellular PKC activity is stimulated. The C-terminal catalytic domain contains several reactive cysteines that are targets for various chemopreventive antioxidants such as selenocompounds, polyphenolic agents such as curcumin, and vitamin E analogues. Modification of these cysteines decreases cellular PKC activity. Thus the two domains of PKC respond differently to two different type of agents: oxidants selectively react with the regulatory domain, stimulate cellular PKC, and signal for tumor promotion and cell growth. In contrast, antioxidant chemopreventive agents react with the catalytic domain, inhibit cellular PKC activity, and thus interfere with the action of tumor promoters.
Gopalakrishna
R
R
Department of Cell and Neurobiology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
Jaken
S
S
D020816:Amino Acid Motifs; D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001585:Benzoyl Peroxide / Q000633:toxicity; D002273:Carcinogens / Q000494:pharmacology / Q000633:toxicity; D020134:Catalytic Domain / Q000187:drug effects; D002396:Catechols / Q000633:toxicity; D003545:Cysteine / Q000737:chemistry; D005609:Free Radicals; D005978:Glutathione / Q000502:physiology; D006131:Growth Inhibitors / Q000494:pharmacology; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity; D006873:Hydroquinones / Q000633:toxicity; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000502:physiology; D018977:Micronutrients / Q000494:pharmacology; D016877:Oxidants / Q000494:pharmacology / Q000502:physiology / Q000633:toxicity; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000502:physiology*; D010766:Phosphorylation; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000502:physiology*; D011499:Protein Processing, Post-Translational; D012643:Selenium / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D012907:Smoking / Q000009:adverse effects; D024505:Tocopherols; D014810:Vitamin E / Q000031:analogs & derivatives / Q000494:pharmacology; D016335:Zinc Fingers / Q000187:drug effects
D016588:Anticarcinogenic Agents; D000975:Antioxidants; D002273:Carcinogens; D002396:Catechols; D005609:Free Radicals; D006131:Growth Inhibitors; D006873:Hydroquinones; D007527:Isoenzymes; D018977:Micronutrients; D016877:Oxidants; D014810:Vitamin E; D006861:Hydrogen Peroxide; D011493:Protein Kinase C; D005978:Glutathione; D012643:Selenium; D003545:Cysteine; D024505:Tocopherols; D001585:Benzoyl Peroxide; C031927:hydroquinone