Yen, Paul M

Research Interests:

Our laboratory has had a long-standing interest in transcriptional regulation by thyroid hormone receptors (TRs) and other nuclear hormone receptors. In particular, we are interested in the recruitment of specific co-factors to thyroid hormone response elements (TREs) and concomitant changes in histone acetylation and methylation in the promoters of individual target genes and the entire genome. Recently, we observed that negative regulation of the glycoprotein hormone α subunit target gene by thyroid hormone surprisingly involves histone acetylation at specific sites. cAMP activates transcription via the same promoter region but involves histone acetylation at other sites. Additonally, we have observed that positive regulation of various target genes by thyroid hormone involves different histone modifications. We currently are using siRNA as well as histone acetyltransferase (HAT) and histone deaetylase (HDAC) inhibitors to determine the critical modifications that determine negative and positive regulation of target genes, We also plan to use ChIP-on-chip and ChIP seq technology to determine the prevalence of such changes across the genome. These studies will be extended to ligand-mediated regulation of other nuclear hormone receptors, including PPAR, LXR, and FXR which play important roles in metabolism and cholesterol regulation.

We also are interested in the cell signaling and cell cycle regulation by PI-3 kinase regulatory subunits, particularly p55 PI3K. Our recent studies have shown that the amino-terminus of p55PI3K (N24) interacts with Rb to regulate cell cycle progression. Using adenovirus expressing N24 and HIV-TAT fusion proteins that contain N24, we have found that N24 peptide inhibits cell proliferation in a wide range of cancer cell lines, and blocks tumor growth in several in vivo cancer models. We currently are studying the mechanisms of N24 effects on cell proliferation, tumor growth, metastasis, and cell redifferentiation. We also plan to screen chemical libraries to find peptidomimetics that may be useful in the treatment of human cancer.

Selected Publications:

Maruvada, P., Baumann, C.T., Hager, G.L., and Yen, P.M. Dynamic shuttling and intranuclear diffusion of nuclear hormone receptors, J. Biol. Chem. 278:12425-12432, 2003.

Yen, P.M., Feng, X., Flamant, F., Chen, Y.D., Samarut, J., Refetoff, S., and Meltzer, P.S. Effects of hormonal status and thyroid hormone receptor (TR) isoforms on hepatic gene expression profiles in TR knockout mice, EMBO Reports 4:581-587, 2003.

Maruvada, P., Dmitrieva, N.I., East-Palmer, J., and Yen P.M. Cell cycle-dependent expression of thyroid hormone receptor-beta is a mechanism for variable hormone sensitivity, Mol. Biol. Cell 15:1895-1903, 2004

Liu, Y., Ando, S., Xia, X., Yao, R.F., Kim, M., Fondell, J., and Yen, P.M. P62, a TFIIH subunit interacts with thyroid hormone receptors (TRs) and enhances T3-mediated transcription, Mol. Endocrinol. 19:879-884, 2005

Liu, Y., Xia, X., Fondell, J.D., and Yen, P.M. Thyroid hormone regulated genes have distinct patterns of co-activator recruitment and histone acetylation, Mol. Endocrinol. 20:483-490, 2006.

Hu, J., Xia, X., Cheng, A., Wang, G., Luo, X., Reed, M.F., Fojo, T.. Oetting, A., Gong, J., Yen P.M. A peptide inhibitor targeting p55PIK PI3K regulatory subunit: a novel cancer therapy. Mol Cancer Therapeutics 7: 3718-3728, 2008.

Wang, D., Xia, X., Liu, Y., Oetting, A, Walker, R.L., Zhu, Y., Meltzer, P., Cole, P.A, Shi, Y.B., Yen P.M. Negative regulation of a target gene by thyroid hormone involves histone acetylation and corepressor complex dissociation. Mol Endocrinol (In Press).