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J Biol Chem, Vol. 274, Issue 33, 23414-23425, August 13, 1999

Involvement of Protein Kinase C (PKC) in Thyroid Cell Death
A TRUNCATED CHIMERIC PKC CLONED FROM A THYROID CANCER CELL LINE PROTECTS THYROID CELLS FROM APOPTOSIS

Jeffrey A. Knauf, Rosella Elisei, Daria Mochly-Rosen^§, Tamar Liron^§, Xiao-Ning Chen^¶, Rivkah Gonsky, Julie R. Korenberg^¶, and James A. Fagin

From the  Division of Endocrinology and Metabolism, University of Cincinnati, Cincinnati, Ohio 45267-0547, the ^§ Department of Molecular Pharmacology, Stanford University, School of Medicine, Stanford, California 94025, the  Division of Endocrinology and Metabolism, and the ^¶ Department of Pediatrics, Medical Genetics Birth Defects Center, Cedars-Sinai Medical Center and UCLA School of Medicine, Los Angeles, California 90048

The protein kinase C (PKC) family has been implicated in the regulation of apoptosis. However, the contribution of individual PKC isozymes to this process is not well understood. We reported amplification of the chromosome 2p21 locus in 28% of thyroid neoplasms, and in the WRO thyroid carcinoma cell line. By positional cloning we identified a rearrangement and amplification of the PKC gene, that maps to 2p21, in WRO cells. This resulted in the overexpression of a chimeric/truncated PKC (Tr-PKC) mRNA, coding for N-terminal amino acids 1-116 of the isozyme fused to an unrelated sequence. Expression of the Tr-PKC protein in PCCL3 cells inhibited activation-induced translocation of endogenous PKC, but its kinase activity was unaffected, consistent with a dominant negative effect of the mutant protein on activation-induced translocation of wild-type PKC and/or displacement of the isozyme to an aberrant subcellular location. Cell lines expressing Tr-PKC grew to a higher saturation density than controls. Moreover, cells expressing Tr-PKC were resistant to apoptosis, which was associated with higher Bcl-2 levels, a marked impairment in p53 stabilization, and dampened expression of Bax. These findings point to a role for PKC in apoptosis-signaling pathways in thyroid cells, and indicate that a naturally occurring PKC mutant that functions as a dominant negative can block cell death triggered by a variety of stimuli.

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