Cell cycle control by the thyroid hormone in neuroblastoma cells.

The thyroid hormone (T3) blocks proliferation and induces differentiation of neuroblastoma N2a-beta cells that overexpress the beta 1 isoform of the T3 receptor. An element in the region responsible for premature termination of transcription mediates a rapid repression of c-myc gene expression by T3. The hormone also causes a decrease of cyclin D1 gene transcription, and is able to antagonize the activation of the cyclin D1 promoter by Ras. In addition, a strong and sustained increase of the levels of the cyclin kinase inhibitor (CKI) p27(Kip1) are found in T3-treated cells. The increased levels of p27(Kip1) lead to a marked inhibition of the kinase activity of the cyclin-CDK2 complexes. As a consequence of these changes, retinoblastoma proteins are hypophosphorylated in T3-treated N2a-beta cells, and progression through the restriction point in the cell cycle is blocked.