Steroid hormones regulate cell function by binding to cytoplasmic receptor proteins. These interact with acceptor sites in target cell nuclei. There they induce messenger RNAs for specific cellular proteins which are responsible for alterations in endocrine physiology. Progesterone has been difficult to study at the molecular level in mammalian systems. We have therefore characterized the progesterone-sensitive chick oviduct over the past 14 years and have shown it to be a representative model of steroid hormone action. The structure-function relationships of the chicken oviduct progesterone receptor will be studied in detail. This hormone binding protein has now been cloned in our laboratory and following expression in suitable vector-host systems will be able to be purified in amounts suitable for detailed protein structural analyses. The protein's subunit structure, DNA binding to the ovalbumin, ovomucoid, and hsp108 genes, hormone-binding mechanism, and effects on endocrine target cells will be studied in vitro. The hormone binding site will be analyzed finally by X-ray crystallography. The origins and relationships of sequence and secondary structure between subunits will be determined, together with detailed analysis of contracts between the two subunits in the intact complex. DNA interactions of subunit A will be defined precisely with respect to effects on DNA higher order structure. A cell-free oviduct transcription system has been developed for tests of effects of purified receptors in vitro using purified transcription factors from homologous oviduct cells. This work should afford us an opportunity to define precisely the molecular basis of hormone-mediated gene expression, resulting in an advance in our understanding of endocrine physiology, reproductive biology and steroid hormone action.

Project Start
1977-05-01
Project End
1997-04-30
Budget Start
1995-05-01
Budget End
1996-04-30
Support Year
24
Fiscal Year
1995
Total Cost
Indirect Cost
Name
Baylor College of Medicine
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
074615394
City
Houston
State
TX
Country
United States
Zip Code
77030
Wang, Lei; Yu, Yang; Chow, Dar-Chone et al. (2015) Characterization of a Steroid Receptor Coactivator Small Molecule Stimulator that Overstimulates Cancer Cells and Leads to Cell Stress and Death. Cancer Cell 28:240-52
Szwarc, Maria M; Lydon, John P; O'Malley, Bert W (2015) Steroid receptor coactivators as therapeutic targets in the female reproductive system. J Steroid Biochem Mol Biol 154:32-8
Wang, Wei; Bian, Ka; Vallabhaneni, Sreeram et al. (2014) ERK3 promotes endothelial cell functions by upregulating SRC-3/SP1-mediated VEGFR2 expression. J Cell Physiol 229:1529-37
Szwarc, Maria M; Kommagani, Ramakrishna; Jeong, Jae-Wook et al. (2014) Perturbing the cellular levels of steroid receptor coactivator-2 impairs murine endometrial function. PLoS One 9:e98664
Putluri, Nagireddy; Maity, Suman; Kommagani, Ramakrishna et al. (2014) Pathway-centric integrative analysis identifies RRM2 as a prognostic marker in breast cancer associated with poor survival and tamoxifen resistance. Neoplasia 16:390-402
Motamed, Massoud; Rajapakshe, Kimal I; Hartig, Sean M et al. (2014) Steroid receptor coactivator 1 is an integrator of glucose and NAD+/NADH homeostasis. Mol Endocrinol 28:395-405
Long, Weiwen; Foulds, Charles E; Qin, Jun et al. (2012) ERK3 signals through SRC-3 coactivator to promote human lung cancer cell invasion. J Clin Invest 122:1869-80
Wang, Ying; Lonard, David M; Yu, Yang et al. (2011) Small molecule inhibition of the steroid receptor coactivators, SRC-3 and SRC-1. Mol Endocrinol 25:2041-53
Li, C; Ao, J; Fu, J et al. (2011) Tumor-suppressor role for the SPOP ubiquitin ligase in signal-dependent proteolysis of the oncogenic co-activator SRC-3/AIB1. Oncogene 30:4350-64
Reddy, Sirigiri Divijendra Natha; Rayala, Suresh K; Ohshiro, Kazufumi et al. (2011) Multiple coregulatory control of tyrosine hydroxylase gene transcription. Proc Natl Acad Sci U S A 108:4200-5

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