Geoffrey L Greene
Research Summary / Selected Publications
The overall goal of my research is to determine the molecular mechanisms by which female steroid hormones regulate development, differentiation, cellular proliferation and survival in hormone responsive tissues and cancers. Estrogens regulate the expression of diverse regulatory proteins and growth factors via one or both of two estrogen receptor subtypes (ERa & ERb). My lab is actively studying several aspects of ER action, including the role of phosphorylation in transcriptional activation of ER, the roles of ER-associated proteins in receptor-mediated responses, the molecular nature of transcriptional activation and/or repression in the regulation of target gene networks, nongenomic actions of estrogens, and the detailed structural requirements for ligand binding to ERa/b, especially in regard to receptor discrimination among selective estrogen receptor modulators (SERMs).
Current areas of focus include: 1) defining the molecular mechanisms by which SERMs elicit tissue-selective agonist or antagonist responses via one or both ER subtypes; 2) identifying novel ER subtype-selective SERMs via a combination of structure-based drug design and de novo drug discovery; 3) generating a mouse model in which ERa is replaced with a mutant ERa that does not recognize endogenous estradiol but will respond normally to a synthetic estrogen such as DES. This model will be useful for studying estrogen-regulated development of the reproductive tract, bone, cardiovasculature and CNS, and will also be used for studying the genesis and progression of hormone dependent mammary cancers; 4) creating mouse models in which ERa, ERb or PR (progesterone receptor) are selectively knocked out in one or more tissues, especially the mammary gland, 4) Determining how ERa suppresses inflammation by inhibiting NF-kB induced cytokine responses, 5) identifying the relative contributions and mechanisms of transcriptional versus rapid, nongenomic ERa/b actions in estrogen target tissue
The overall goal of my research is to determine the molecular mechanisms by which female steroid hormones regulate development, differentiation, cellular proliferation and survival in hormone responsive tissues and cancers. Estrogens regulate the expression of diverse regulatory proteins and growth factors via one or both of two estrogen receptor subtypes (ERa & ERb). My lab is actively studying several aspects of ER action, including the role of phosphorylation in transcriptional activation of ER, the roles of ER-associated proteins in receptor-mediated responses, the molecular nature of transcriptional activation and/or repression in the regulation of target gene networks, nongenomic actions of estrogens, and the detailed structural requirements for ligand binding to ERa/b, especially in regard to receptor discrimination among selective estrogen receptor modulators (SERMs).
Current areas of focus include: 1) defining the molecular mechanisms by which SERMs elicit tissue-selective agonist or antagonist responses via one or both ER subtypes; 2) identifying novel ER subtype-selective SERMs via a combination of structure-based drug design and de novo drug discovery; 3) generating a mouse model in which ERa is replaced with a mutant ERa that does not recognize endogenous estradiol but will respond normally to a synthetic estrogen...
Hsieh, R. W., Rajan, S. S., Sharma, S. K., Guo, Y., DeSombre, E. R., Mrksich, M. and Greene, G. L. (2006). "Identification of ligands with bicyclic scaffolds provides insights into mechanisms of estrogen receptor subtype selectivity." J Biol Chem 281: 17909-19.
Huang, J., Koide, A., Nettle, K. W., Greene, G. L. and Koide, S. (2006). "Conformation-specific affinity purification of proteins using engineered binding proteins: application to the estrogen receptor." Protein Expr Purif 47: 348-54.
Yeo, W. S., Min, D. H., Hsieh, R. W., Greene, G. L. and Mrksich, M. (2005). "Label-free detection of protein-protein interactions on biochips." Angew Chem Int Ed Engl 44: 5480-3.
Wu, Y. L., Yang, X., Ren, Z., McDonnell, D. P., Norris, J. D., Willson, T. M. and Greene, G. L. (2005). "Structural basis for an unexpected mode of SERM-mediated ER antagonism." Mol Cell 18: 413-24.
Nettles, K. W. and Greene, G. L. (2005). "Ligand control of coregulator recruitment to nuclear receptors." Annu Rev Physiol 67: 309-33.
Leong, H., Sloan, J. R., Nash, P. D. and Greene, G. L. (2005). "Recruitment of histone deacetylase 4 to the N-terminal region of estrogen receptor alpha." Mol Endocrinol 19: 2930-42.
Nettles, K.W., et al., Allosteric control of ligand selectivity between estrogen receptors alpha and beta: implications for other nuclear receptors. Mol Cell, 2004. 13(3): p. 317-27.
Hsieh, R. W., Rajan, S. S., Sharma, S. K., Guo, Y., DeSombre, E. R., Mrksich, M. and Greene, G. L. (2006). "Identification of ligands with bicyclic scaffolds provides insights into mechanisms of estrogen receptor subtype selectivity." J Biol Chem 281: 17909-19.
Huang, J., Koide, A., Nettle, K. W., Greene, G. L. and Koide, S. (2006). "Conformation-specific affinity purification of proteins using engineered binding proteins: application to the estrogen receptor." Protein Expr Purif 47: 348-54.
Yeo, W. S., Min, D. H., Hsieh, R. W., Greene, G. L. and Mrksich, M. (2005). "Label-free detection of protein-protein interactions on biochips." Angew Chem Int Ed Engl 44: 5480-3.
Wu, Y. L., Yang, X., Ren, Z., McDonnell, D. P., Norris, J. D., Willson, T. M. and Greene, G. L. (2005). "Structural basis for an unexpected mode of SERM-mediated ER antagonism." Mol Cell 18: 413-24.
Nettles, K. W. and Greene, G. L. (2005). "Ligand control of coregulator recruitment to nuclear receptors." Annu Rev Physiol 67: 309-33.
