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Molecular and Cellular Biology, October 2001, p. 6626-6639, Vol. 21, No. 19
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.19.6626-6639.2001

Silencing of Wnt Signaling and Activation of Multiple Metabolic Pathways in Response to Thyroid Hormone-Stimulated Cell Proliferation

Lance D. Miller,1 Kyung Soo Park,2 Qingbin M. Guo,1,dagger Nawal W. Alkharouf,1 Renae L. Malek,3 Norman H. Lee,3 Edison T. Liu,1 and Sheue-yann Cheng2,*

Section of Molecular Signaling and Oncogenesis, Medicine Branch, Division of Clinical Sciences,1 and Laboratory of Molecular Biology,2 National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, and The Institute for Genomic Research, Department of Functional Genomics, Rockville, Maryland 208503

Received 6 February 2001/Returned for modification 9 May 2001/Accepted 2 July 2001

To investigate the transcriptional program underlying thyroid hormone (T3)-induced cell proliferation, cDNA microarrays were used to survey the temporal expression profiles of 4,400 genes. Of 358 responsive genes identified, 88% had not previously been reported to be transcriptionally or functionally modulated by T3. Partitioning the genes into functional classes revealed the activation of multiple pathways, including glucose metabolism, biosynthesis, transcriptional regulation, protein degradation, and detoxification in T3-induced cell proliferation. Clustering the genes by temporal expression patterns provided further insight into the dynamics of T3 response pathways. Of particular significance was the finding that T3 rapidly repressed the 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 cell proliferation is accompanied by a complex coordinated transcriptional reprogramming of many genes in different pathways and that early silencing of the Wnt pathway may be critical to this event.

* Corresponding author. Mailing address: Laboratory of Molecular Biology, Building 37, Room 2D24, 37 Convent Dr., MSC 4255, National Cancer Institute, Bethesda, MD 20892-4255. Phone: (301) 496-4280. Fax: (301) 480-9676. E-mail: sycheng{at}helix.nih.gov.

dagger Present address: Division of Cancer Biology, Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21205.

Molecular and Cellular Biology, October 2001, p. 6626-6639, Vol. 21, No. 19
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.19.6626-6639.2001


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