The major interest of our laboratory is to characterize novel functions for reversible protein acetylation in signal transduction and human diseases. We have taken a reverse genetics approach and focused our research on characterizing the functions of novel protein deacetylases (HDACs). This approach has led to the discovery of surprisingly complex functions and regulations of protein acetylation. For example, we have identified HDAC6 as a cytoplasmic deacetylase that dynamically associates with the microtubule and actin cytoskeleton in response to growth factor signaling, and controls cell motility and endocytosis: two interconnected processes intimately linked to cancer metastasis. HDAC6 and the closely related HDAC10 also regulate the microtubule-dependent transport and processing of toxic misfolded protein aggregates, a dominant cause of pathological neuronal cell death, implicating an important role for these enzymes in neurodegenerative diseases. In contrast, we have found that HDAC4 undergoes active nucleus-cytoplasm shuttling in response to specific signaling events that controls neuronal survival as well as muscle differentiation. These complex cellular and biochemical behaviors of HDAC members reveal a rich biology of protein acetylation and provide the mechanistic basis for the broad interest in the therapeutic potential of HDAC inhibitors in cancer and neurodegenerative diseases.

The ongoing work in the lab aims to further understand the mechanism through which HDAC regulates cell migration, oncogenic transformation and neuronal cell death, and to identify novel HDAC substrates and acetyltransferases involved in these important biological processes. We are also using mouse genetic model to delineate the role of HDAC family members in cancer formation and neurodegenerative disease as well as their potential utility in developing novel therapies. Our ultimate goal is to establish a comprehensive understanding of this versatile protein modification in cell signaling and human disease.

Ito, A., Lai, C.-H, Zhao, X., Huacani, M.R., Saito, S., Appella, E., and Yao , T.-P . p300/CBP mediated- p53 acetylation is commonly induced by p53 activating agents and inhibited by mdm2. EMBO J . 20, 1331-1340 (2001)

Zhao, X., Ito, A., Kane, C., Liao, V., Bolger, T. A., Lemrow, S. M., Means, A.R, and Yao , T.-P . The modular nature of histone deacetylase HDAC4 confers phosphorylation-dependent intracellular trafficking J. Biol. Chem. 276, 35042-8 (2001)

Guardiola, A. and Yao , T.-P . Molecular cloning and characterization of a novel class II histone deacetylase HDAC10. J. Biol. Chem. 277, 3350-6 (2002)

Ito, A. Kawaguchi, Y., Lai, C.-H, Kovacs, J. J., Higashimoto, Y., Appella, E., and Yao , T.-P. MDM2-HDAC1 mediated-deacetylation of p53 is required for its degradation. EMBO. J . 22. 6236-6245 (2002)

Hubbert, C ., Guardiola, A. , Shao, R., Kawaguchi, Y., Ito, A., Yoshida, M., Wang, X.F. and Yao , T.-P . Identification of HDAC6 as a microtubule-associated deacetylase. Nature 417, 455-458 (2002)

Kawaguchi, Y., Kovacs, J. J. , McLaurin, A., Vance, J. M., Ito, A., and Yao , T.-P. . The deacetylase HDAC6 regulates aggresome formation and cell viability in response to misfolded protein stress. Cell. 115. 727-738 (2003)

Kovacs, J.J., Murphy, P. J., Stephanie Gaillard, Zhao, X., , Wu, J.-T., Nicchitta, C., Yoshida, M., Toft, D., Pratt, W., and Yao , T.-P. . The deacetylase HDAC6 regulates Hsp90 acetylation and chaperone -dependent activation of glucocorticoid receptor. Molecular Cell 18(5) 601-607 (2005)

Zhao, X., Sternsodorf, T., Bolger, T. A., Evans, R. M. and Yao, T.-P. Regulation of MEF2 by class II and class III histone deacetylases mediated lysine modifications. Mol. Cell Biol. 25(19):8456-64 (2005)

Bolger, T.A., and Yao, T.-P. Intracellular trafficking of Histone deacetylase 4 regulates neuronal cell death J. Neuroscience 25(41):9544-53 (2005)