Endocrinology, Vol 137, 96-104, Copyright © 1996 by Endocrine Society

ARTICLES

Ras inhibits thyroglobulin expression but not cyclic adenosine monophosphate-mediated signaling in Wistar rat thyrocytes

E Kupperman, D Wofford, W Wen and JL Meinkoth
Department of Medicine, University of California at San Diego, La Jolla 92093, USA.

We previously reported that microinjection of purified Ras protein stimulated DNA synthesis in quiescent Wistar rat thyrocytes and that TSH (TSH)-stimulated DNA synthesis was Ras-dependent. In contrast to these results, microinjection of cellular or oncogenic Ras significantly reduced TSH-stimulated thyroglobulin (Tg) expression, a marker of thyrocyte differentiation. Microinjection of a dominant inhibitory Ras mutant had no effect on TSH-stimulated Tg expression. As the Tg promoter is cAMP-responsive and Ras was previously reported to interfere with entry of catalytic (C) subunit of the cAMP-dependent protein kinase into the nucleus, experiments were performed to assess the effects of Ras on cAMP-mediated signaling. Microinjection of either cellular or oncogenic Ras had no effect on TSH-stimulated entry of C subunit into the nucleus. Consistent with these data, Ras did not reduce TSH-stimulated cAMP response element binding protein phosphorylation, or cAMP response element-regulated gene expression. These results demonstrate that Ras exerts differential effects on TSH signaling; Ras increases TSH-stimulated DNA synthesis and decreases TSH- induced Tg expression. Moreover, the mechanism through which Ras induces Tg expression lies distal to entry of C subunit into the nucleus, cAMP response element binding protein phosphorylation, and cAMP response element-regulated gene expression.

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