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J Biol Chem, Vol. 273, Issue 43, 28392-28398, October 23, 1998

Induction of Thymocyte Apoptosis by Ca²⁺-independent Protein Kinase C (nPKC) Activation and Its Regulation by Calcineurin Activation

Akiko Asada, Yong Zhao, Shunzo Kondo, and Makoto Iwata

From the  Integrative Projects and  Electron Microscopy Section, Mitsubishi Kasei Institute of Life Sciences, 11 Minamiooya, Machida-shi, Tokyo 194, Japan

Glucocorticoids appear to participate in apoptosis of unselected CD4⁺CD8⁺ thymocytes. Activation of Ca²⁺-independent novel protein kinase C (nPKC) precedes glucocorticoid-induced thymocyte apoptosis, while proper levels of Ca²⁺-dependent protein kinase C (cPKC) and calcineurin activities contribute to rescue thymocytes. To clarify the role of nPKC in thymocyte apoptosis, murine thymocytes were stimulated with the diterpene diester, ingenol 3,20-dibenzoate (IDB). IDB induced selective translocation of nPKC-, -, and - and PKC-µ from the cytosolic fraction to the particulate fraction and induced morphologically typical apoptosis through de novo synthesis of macromolecules. The apoptosis was also induced by thymeleatoxin, a diterpene ester, at relatively high concentrations that induced translocation of cPKC, nPKC-, and PKC-µ. The IDB- or thymeleatoxin-induced death was inhibited by non-isoform-selective PKC inhibitors, but not by their structural analogs with weak PKC-inhibitory activity or the selective inhibitor of cPKC and PKC-µ, Gö 6976. The death was also inhibited by calcium ionophore ionomycin at concentrations within a narrow range. The range corresponded to the concentration range that contributes to the inhibition of glucocorticoid-induced apoptosis. The antiapoptotic effect was canceled by the immunosuppressant FK506 but not by rapamycin. These results indicate that activation of nPKC, especially nPKC-, induces apoptosis in thymocytes and that calcineurin activation regulates the apoptosis.

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