Regulation of type 3 iodothyronine deiodinase expression in cultured rat astrocytes: Role of the Erk cascade

The type 3 iodothyronine deiodinase (D3) metabolizes thyroid hormones to in active metabolites in many tissues, including the brain. In the present stu dies, we have examined the mechanisms by which T-3 (T-3), retinoic acid, 12 -O-tetradecanoyl phorbol 13-acetate (TPA), and basic fibroblast growth fact or (bFGF) induce D3 expression in primary cultures of neonatal rat astrocyt es. In untreated cells, D3 messenger RNA (mRNA) was essentially undetectabl e by Northern analysis and RT-PCR. However, all four agents induced express ion of a 2.4-kb D3 transcript as well as D3 activity. Induction of D3 by TP A and bFGF was more rapid than that by T-3 and retinoic acid, and T-3 poten tiated the stimulatory effects of TPA and bFGF. D3 induction by TPA was blo cked by GF 109203X, an inhibitor of protein kinase C. In addition, the effe cts of TPA and bFGF were partially prevented by PD 98059, a specific inhibi tor of MEK and the Erk signaling cascade. These studies demonstrate that mu ltiple growth factors and hormones regulate D3 activity in cultured astrocy tes by inducing D3 mRNA expression. In addition, the stimulatory effects of TPA and bFGF on D3 mRNA and activity appear to be mediated at least in par t by activation of the MEK/Erk signaling cascade.