Z. Dave
Sharp,
Ph.D.
Professor and Department Chairman
Profile and Contact Information |
Research
| Laboratory
RESEARCH
Research Program
The major research interests of my laboratory are: 1) the role of the retinoblastoma protein in the regulation of insulin like growth factor-I (IGF-I) and nutrient signaling through mammalian TOR pathways; 2) understanding the function of a transcription factor vital to pituitary development called Pit-1.
We recently published data showing that dietary restriction is not effective in delaying the development or inhibiting the growth of spontaneous neuroendocrine tumors (pituitary and thyroid) in Rb+/- mice. One of the leading hypotheses to explain the almost universal ability of diet restriction to retard tumor growth is a reduction of endocrine IGF-I. Because diet restricted (50%) Rb+/- mice were smaller than those in the ad libitum group, it is clear that this reduced level of energy was effective in retarding overall growth in Rb+/- tissues and organs. Since tumors lose Rb heterozygosity (Rb-/-) in the very early stages of tumorigenesis, the data suggest that the retinoblastoma protein is somehow required for the response to reduced calories. Combined with other data linking Rb to somatic growth, we developed the postulate that the retinoblastoma protein negatively regulates IGF-I and nutrient signaling through the mammalian target of rapamycin (mTOR) kinase. Current tests include assays of IGF-I signaling in Rb-/- tumors compared to surrounding Rb+/- tissues, and ex vivo experiments using Rb silencing in combination with IGF-I stimulation to determine if IGF-I signaling is repressed when the retinoblastoma protein is present. These studies will elucidate the interaction of two important factors, Rb, a suppressor of cancer, and IGF-I, a promoter. My collaborator in this study is Phang-Lang Chen.
Pit-1, a founding member of the POU-family of developmentally regulated transcription factors, is critical for the differentiation and survival of three of the pituitary cell types; somatotropes (growth hormone), lactotropes (prolactin) and thyrotropes (thyroid stimulating hormone ?). Humans and rodents deficient in Pit-1 function have a combined pituitary hormone deficiency resulting in dwarfism and, in rodents, infertility. Pit-1 function depends upon synergistic activation of target genes (e.g., prolactin and growth hormone) in conjunction with other transcription factors. Some of the most important of these co-activators are the estrogen receptor ? (ER ?, prolactin), and thyroid hormone, retinoic acid and retinoid X receptors for growth hormone transcription. The goal is to understand how Pit-1 and these nuclear receptors synergistically activate transcription. For this purpose we are using live and fixed cell biological methods combined with biochemical approaches. Collaborators in these studies are Mike Mancini in the Department of Cell and Molecular Biology at the Baylor College of Medicine and Kelly Smith, in the Department of Cell Biology at the University of Massachusetts Medical School. We have recently published that nuclear dynamics (mobility) of Pit-1 is important for it ability to function as a transcription factor, and that overexpression of mutated Pit-leads to its immobility and elicitation of a heat shock-type nuclear response.
Selected Publications
- Sharp, Z.D., Lee, W.-H., Nikitin, A.Y., Flesken-Nikitin, A., Ikeno, Y., Reddick, R., Richardson, A.G. and Nelson, J.F. Minimal effects of dietary restriction on neuroendocrine carcinogenesis in Rb+/- mice. Carcinogenesis 24: 179-183, 2003.
- Sharp, Z.D., Stenoien, D.L., Mancini, M.G., Ouspenski, I.I. and Mancini, M.A. Inactivating Pit-1 mutations alter subnuclear dynamics suggesting a protein misfolding and nuclear stress response. J. Cell. Biochem. 92: 664-678, 2004.
- Hinojos, C.A.D., Sharp, Z.D. and Mancini, M.A. (2005) Molecular dynamics and nuclear receptor function. Trends in Endocrinology and Metabolism 16: 12-18.
- Sharp, Z.D. and Bartke, A. (2005) Evidence for down regulation of PI3K/Akt/mTOR-dependent translation regulatory signaling pathways in Ames dwarf mice. J. Gerontology (A. Biol. Sci. Med. Sci.) 60: 293-300.
- Sharp, Z.D., Mancini, M.G., Hinojos, C., Dai, F., Berno, V., Szafran, A., Smith, K.P., Lele, T., Ingber, D., and Mancini, M.A. (2006) Estrogen receptor-alpha exchange and chromatin dynamics and ligand- and domain-dependent. J. Cell Science 119:4101-4116.
- Mancini, M.A. and Sharp, Z.D. Visualizing the Dynamic Interactions of Nuclear Receptors. In revision, Mol. Endocrinol.
- Sharp, Z.D., M. G. Mancini, M.G., Dai, F., Hinojos, C., Szafran, A., Kelly P. Smith, K.P., Lee, T., Ingber, D. and Mancini, M.A. Visible synergistic transcription factor interactions with an integrated prolactin promoter/enhancer array. Submitted to Nature Cell Biol.