Silencing of Wnt signaling and activation of multiple metabolic pathways in response to thyroid hormone-stimulated cell proliferation

To investigate the transcriptional program underlying thyroid hormone (T3)- induced cell proliferation, cDNA microarrays were used to survey the tempor al expression profiles of 4,400 genes. Of 358 responsive genes identified, 88% had not previously been reported to be transcriptionally or functionall y modulated by T3. Partitioning the genes into functional classes revealed the activation of multiple pathways, including glucose metabolism, biosynth esis, transcriptional regulation, protein degradation, and detoxification i n T3-induced cell proliferation. Clustering the genes by temporal expressio n patterns provided further insight into the dynamics of T3 response pathwa ys. Of particular significance was the finding that T3 rapidly repressed th e expression of key regulators of the Wnt signaling pathway and suppressed the transcriptional downstream elements of the beta -catenin-T-cell factor complex. This was confirmed biochemically, as beta -catenin protein levels also decreased, leading to a decrease in the transcriptional activity of a beta -catenin-responsive promoter. These results indicate that T3-induced c ell proliferation is accompanied by a complex coordinated transcriptional r eprogramming of many genes in different pathways and that early silencing o f the Wnt pathway may be critical to this event.