Atypical protein kinase C-zeta 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 PKCzeta, a phorbol ester-unresponsive isozyme, in cell proliferation, death, and survival. We overexpressed PKCzeta in Wistar rat thyroid (WRT) cells and determined that PKCzeta conferred TSH-independent DNA synthesis and cell proliferation. Cells overexpressing PKCzeta show higher levels of phosphorylated p42/p44 MAPK compared with vector-transfected cells. Experiments using a luciferase reporter for Elk-1 revealed that PKCzeta 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 PKCzeta. Strikingly, TSH retained the ability to stimulate Tg expression in cells expressing PKCzeta. These results suggest that PKCzeta stimulates TSH-independent mitogenesis through a p42/p44 MAPK-dependent pathway. Unlike overexpression of Ras or phorbol ester treatment, PKC overexpression does not impair thyroglobulin (Tg) expression.
Fernandez
N
N
Center for Experimental Therapeutics, University of Pennsylvania School of Medicine, Philadelphia 19104-6160, USA.
Caloca
M J
MJ
Prendergast
G V
GV
Meinkoth
J L
JL
Kazanietz
M G
MG
D000818:Animals; D015153:Blotting, Western; D002455:Cell Division; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis; D004268:DNA-Binding Proteins; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics / Q000502:physiology; D005822:Genetic Vectors / Q000235:genetics; D019950:Mitogen-Activated Protein Kinase 1 / Q000502:physiology; D011493:Protein Kinase C / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D013961:Thyroid Gland / Q000166:cytology*; D013972:Thyrotropin / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics; D050807:ets-Domain Protein Elk-1; D000099221:Protein Kinase C zeta
D004247:DNA; D004268:DNA-Binding Proteins; D019950:Mitogen-Activated Protein Kinase 1; D011493:Protein Kinase C; D011518:Proto-Oncogene Proteins; D013972:Thyrotropin; D014157:Transcription Factors; D050807:ets-Domain Protein Elk-1; D000099221:Protein Kinase C zeta; C494114:Elk1 protein, rat