RAS INHIBITS THYROGLOBULIN EXPRESSION BUT NOT CYCLIC ADENOSINE MONOPHOSPHATE-MEDIATED SIGNALING IN WISTAR RAT THYROCYTES

We previously reported that microinjection of purified Ras protein sti mulated 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 re duced TSH-stimulated thyroglobulin (Tg) expression, a marker of thyroc yte differentiation. Microinjection of a dominant inhibitory Ras mutan t had no effect on TSH-stimulated Tg expression. As the Tg promoter is cAMP-responsive and Ras was previously reported to interfere with ent ry of catalytic (C) subunit of the cAMP-dependent protein kinase into the nucleus, experiments were performed to assess the effects of Ras o n cAMP-mediated signaling. Microinjection of either cellular or oncoge nic Ras had no effect on TSH-stimulated entry of C subunit into the nu cleus. Consistent with these data, Ras did not reduce TSH-stimulated c AMP 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-stimu lated 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 pro tein phosphorylation, and cAMP response element-regulated gene express ion.