Steroid hormones stimulate growth, maturation and the development of new biochemical capacities in their endocrine target organs and are keys to understanding multiple diseases. They act by binding to their cognate nuclear receptors and recruiting a series of coregulator (coactivator/corepressor) proteins that carry out all substeps of transcription and also influence non-nuclear functions of the hormones. Although the basic overall pathways by which sex steroids exert their biochemical actions are known, the detailed mechanisms by which they act to regulate functions in normal and pathological tissues remain elusive. For example, in the past 12 years, we have discovered the existence of NR coactivators, determined how they function at various steps of chromatin remodeling and transcription, and realized their enormous potential in influencing the initiation and progression of disease. Now, we need to understand the mechanisms by which coactivators function in precise detail. For example, how does one coactivator perform so many different important functions in mammalian tissues? How does a coactivator become `activated'to form distinct multimeric coactivator complexes for cellular functions? How does a coactivator differentially bind to NRs (or other transcription factors) for transcriptional activation at select promoters? How does a coactivator direct distinct subreactions of transcription (eg., chromatin remodeling, transcriptional initiation, RNA chain elongation, RNA splicing, termination, etc.)? How can one coactivator participate in regulating molecular substeps of transcription on one hand, and then on the other hand, function in totally different cellular compartments to control mRNA translation, mitochondrial biology, or membrane initiated cell motility? Finally, how does the same coregulator function as a `coactivator'in certain instances, and as a `corepressor'in other instances? Even more perplexing, how can a specific coactivator function as a stimulator (eg., oncogene) in certain cell contexts and a repressor (eg., tumor suppressor) in others? We are excited to have recently discovered that the secret to these functions lies in the `posttranslational modification (PTM) coding'of coactivators. It is our belief that understanding this PTM coding, will disclose the mechanistic secrets of all normal function and the information required for the diagnosis and treatment and prevention of myriad endocrine and reproductive diseases.

Public Health Relevance

Steroid hormones stimulate growth, maturation and the development of new biochemical capacities in their endocrine target organs and are keys to understanding multiple diseases. They act by binding to their cognate nuclear receptors and recruiting a series of coregulator (coactivator/corepressor) proteins that carry out all substeps of transcription and also influence non-nuclear functions of the hormones.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD008188-41
Application #
8435307
Study Section
Molecular and Cellular Endocrinology Study Section (MCE)
Program Officer
Yoshinaga, Koji
Project Start
1974-09-01
Project End
2014-02-28
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
41
Fiscal Year
2013
Total Cost
$583,565
Indirect Cost
$203,392
Name
Baylor College of Medicine
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Feng, Qin; Zhang, Zheng; Shea, Martin J et al. (2014) An epigenomic approach to therapy for tamoxifen-resistant breast cancer. Cell Res 24:809-19
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
Wang, Ying; Lonard, David M; Yu, Yang et al. (2014) Bufalin is a potent small-molecule inhibitor of the steroid receptor coactivators SRC-3 and SRC-1. Cancer Res 74:1506-17
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
Stashi, Erin; York, Brian; O'Malley, Bert W (2014) Steroid receptor coactivators: servants and masters for control of systems metabolism. Trends Endocrinol Metab 25:337-47
York, Brian; Sagen, Jørn V; Tsimelzon, Anna et al. (2013) Research resource: tissue- and pathway-specific metabolomic profiles of the steroid receptor coactivator (SRC) family. Mol Endocrinol 27:366-80
Foulds, Charles E; Feng, Qin; Ding, Chen et al. (2013) Proteomic analysis of coregulators bound to ER* on DNA and nucleosomes reveals coregulator dynamics. Mol Cell 51:185-99
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
Johnson, Amber B; O'Malley, Bert W (2012) Steroid receptor coactivators 1, 2, and 3: critical regulators of nuclear receptor activity and steroid receptor modulator (SRM)-based cancer therapy. Mol Cell Endocrinol 348:430-9
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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