Atypical protein kinase C-ζ stimulates thyrotropin-independent proliferation in rat thyroid cells

Several reports have indicated that protein kinase C (PKC) is an important regulator of proliferation in thyroid cells. Unlike TSH, the mitogenic effects of phorbol esters are accompanied by de-differentiation. The role of individual PKC isoforms in thyroid cell proliferation and differentiation has not been examined. Recent studies have implicated the atypical PKC zeta, a phorbol ester-unresponsive isozyme, in cell proliferation, death, and survival. We overexpressed PKC zeta in Wistar rat thyroid (WRT) cells and determined that PKC zeta conferred TSH-independent DNA synthesis and cell proliferation. Cells overexpressing PKC zeta show higher levels of phosphorylated p42/p44 MAPK compared with vector-transfected cells. Experiments using a luciferase reporter for Elk-l revealed that PKC zeta overexpressing cells exhibit higher basal Elk-l transcriptional activity than vector-transfected control cells. Interestingly, stimulation of Elk-1 transcriptional activity by MEK1, a p42/p44 MAPK kinase, was significantly enhanced in cells overexpressing PKC zeta. Strikingly, TSH retained the ability to stimulate Tg expression in cells expressing PKC zeta. These results suggest that PKC zeta stimulates TSH-independent mitogenesis through a p42/p44 MAPK-dependent pathway. Unlike overexpression of Ras or phorbol ester treatment, PKC zeta overexpression does not impair thyroglobulin (Tg) expression.