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

Abstract

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 PKCζ, a phorbol ester-unresponsive isozyme, in cell proliferation, death, and survival. We overexpressed PKCζ in Wistar rat thyroid (WRT) cells and determined that PKCζ conferred TSH-independent DNA synthesis and cell proliferation. Cells overexpressing PKCζ show higher levels of phosphorylated p42/p44 MAPK compared with vector-transfected cells. Experiments using a luciferase reporter for Elk-1 revealed that PKCζ overexpressing cells exhibit higher basal Elk-1 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 PKCζ. Strikingly, TSH retained the ability to stimulate Tg expression in cells expressing PKCζ. These results suggest that PKCζ stimulates TSH-independent mitogenesis through a p42/p44 MAPK-dependent pathway. Unlike overexpression of Ras or phorbol ester treatment, PKCζ overexpression does not impair thyroglobulin (Tg) expression.