Steroids, vitamins, retinoids, and thyroid hormones exert profound effects on cell growth, development, differentiation, homeostasis and tumorigenesis through their cognate nuclear receptors which make up a superfamily of structurally related intracellular hormone-activated transcription factors. Recent evidence suggests that transcriptional regulation by nuclear hormone receptors (NHRs) require a diverse group of proteins termed co-activators. Co-activators portray a growing class of proteins that interact with receptors in a hormone-dependent manner and are required for maximal gene activation by the receptors. It is the general belief that co-activators enhance receptor function by acting as a bridge between the DNA-bound receptor and basal transcription factors of the pre-initiation complex and also by providing histone acetyl transferase activity, HAT, which disrupts the local repressive chromatin structure and contributes to increase transcriptional activity. Recently, our laboratory and other have cloned ubiquitin-proteasome and ubiquitin-like (NEDD8, neural precursor cell-expressed developmentally down-regulated) pathway enzymes, E6-associated protein (E6-AP), RSP5/RPF1, ubiquitin- conjugating enzymes (UBCs), SUG1 and E1 ubiquitin-activating enzymes (UBA3) as co-activators of NHRs. These co-activators possess other enzymatic activities such as ubiquitin activation, ubiquitination conjugation, ubiquitin ligation and protease activities, instead of HAT activity. These observations suggest a possible regulatory role for the ubiquitin and NEDD8 pathways in nuclear hormone receptor-mediated gene activation. However, the exact mechanisms by which these pathways regulate nuclear receptor gene activation is completely unknown at this time. Based on our preliminary observations, we hypothesize that the ubiquitin and NEDD8 pathways are modulators of nuclear hormone receptor co-activation. In order to understand the mechanism by which these pathways modulate nuclear hormone receptor gene activation, we propose the following three specific aims: A) To identify and characterize the E6-AP interacting protein(s) and study their role along with E6-AP in nuclear hormone receptor co-activation, B) To identify and characterize target proteins of the ubiquitin-proteasome pathway and understand the mechanism by which these pathways modulate nuclear hormone receptor gene activation, we propose the following three specific aims: A) To identify and characterize the E6-AP interacting protein(s) and study their role along with E6-AP in nuclear hormone receptor co-activation, B) To identify and characterize target proteins of the ubiquitin-proteasome pathway and understand the mechanism by which this pathway modulates nuclear hormone receptor gene activation, and C) To characterize the E1 ubiquitin-activating enzyme, UBA3,. Of the NEDD8 pathway as a co-activator of NHRs and to characterize this role in nuclear hormone receptor co-activation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK056833-01
Application #
6033599
Study Section
Biochemical Endocrinology Study Section (BCE)
Program Officer
Margolis, Ronald N
Project Start
2000-02-01
Project End
2004-01-31
Budget Start
2000-02-01
Budget End
2001-01-31
Support Year
1
Fiscal Year
2000
Total Cost
$198,058
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
Khan, Obaid Y; Fu, Guilian; Ismail, Ayesha et al. (2006) Multifunction steroid receptor coactivator, E6-associated protein, is involved in development of the prostate gland. Mol Endocrinol 20:544-59
Dhananjayan, Sarath C; Ramamoorthy, Sivapriya; Khan, Obaid Y et al. (2006) WW domain binding protein-2, an E6-associated protein interacting protein, acts as a coactivator of estrogen and progesterone receptors. Mol Endocrinol 20:2343-54
Ismail, Ayesha; Nawaz, Zafar (2005) Nuclear hormone receptor degradation and gene transcription: an update. IUBMB Life 57:483-90
Dhananjayan, Sarath C; Ismail, Ayesha; Nawaz, Zafar (2005) Ubiquitin and control of transcription. Essays Biochem 41:69-80
Gao, Xiuhua; Mohsin, Syed K; Gatalica, Zoran et al. (2005) Decreased expression of e6-associated protein in breast and prostate carcinomas. Endocrinology 146:1707-12
Verma, Seema; Ismail, Ayesha; Gao, Xiuhua et al. (2004) The ubiquitin-conjugating enzyme UBCH7 acts as a coactivator for steroid hormone receptors. Mol Cell Biol 24:8716-26
Nawaz, Zafar; O'Malley, Bert W (2004) Urban renewal in the nucleus: is protein turnover by proteasomes absolutely required for nuclear receptor-regulated transcription? Mol Endocrinol 18:493-9
Pearce, Virginia; Nawaz, Zafar; Xiao, Wu et al. (2003) 4-ethoxymethylphenol: a novel phytoestrogen that acts as an agonist for human estrogen receptors. J Steroid Biochem Mol Biol 84:431-9
Khan, Obaid Yusuf; Nawaz, Zafar (2003) Nuclear hormone receptor co-regulators. Curr Opin Drug Discov Devel 6:692-701
Yan, Feng; Gao, Xiuhua; Lonard, David M et al. (2003) Specific ubiquitin-conjugating enzymes promote degradation of specific nuclear receptor coactivators. Mol Endocrinol 17:1315-31

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