Hormone signaling such as estrogen-stimulated cell proliferation and differentiation in female reproductive tissues involves dynamic processes of gene expression. In mouse uterus, as well as in human endometrial cancer and breast cancer cells, estrogen stimulation results in cascades of gene expression that leads to marked cell proliferation. In addition, estrogen receptor-alpha (ERa) mediated activation of gene transcription also entails a dynamic assembly of nuclear cofactors that are required for facilitating the transcriptional regulation. Among all the protein factors involved in the dynamic regulation processes, nuclear cofactors may play a key role. Indeed our previous studies indicate that ACTR, one of the p160/SRC cofactors, can function as a coactivator for both ERa and the activator E2Fs, therefore linking closer the transcriptional programs of estrogen signaling and cell cycle control. During the course of our study, we found that a novel nuclear cofactor ATAAB is highly induced by estrogen in ERa-positive cancer cells as well as in the epithelium of mouse uterus and mammary gland. Consistent with its critical role in estrogen signaling, we found that ATAAB can act as an ERa coactivator. These and other findings led to the hypothesis that estrogen stimulation of cell proliferation involves the activation of a novel nuclear factor ATAAB, which functions by directing ER to specific target genes and subsequently remodeling the ER- coactivator complexes. We will test the hypothesis in the following Specific Aims:
in Aim 1, we will determine the role of ATAAB in directing and integration of E2-induced transcription program for cell proliferation.
In Aim 2, we will determine the functional mechanism of ATAAB in mediating ER-ACTR control of gene transcription.
In Aim 3, we will examine the physiological and pathological function of ATAAB. We will apply biochemistry, molecular genetics and endocrinology approaches to achieve the goals. It is anticipated that results from the proposed study will provide novel insights to the underlying molecular mechanisms of steroid receptor function in female reproduction and breast cancers as well as other endocrine disorders. Hormones such as estrogen play crucial roles in the growth and function of female reproductive tissues and in breast cancer. These biological effects are largely mediated by the hormone receptor which controls specific gene expression. The process of estrogen receptor mediated activation of gene transcription is highly regulated by the function of nuclear cofactor proteins. This proposed study will examine how the nuclear cofactors work together with the receptor and other nuclear protein to control gene expression and the biological effects of estrogen. Understanding the process will provide novel insights to the underlying molecular mechanisms of steroid receptor function in female reproduction and breast cancers as well as other endocrine disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK060019-10
Application #
8233939
Study Section
Molecular and Cellular Endocrinology Study Section (MCE)
Program Officer
Margolis, Ronald N
Project Start
2001-07-01
Project End
2014-02-28
Budget Start
2012-03-01
Budget End
2014-02-28
Support Year
10
Fiscal Year
2012
Total Cost
$297,950
Indirect Cost
$101,930
Name
University of California Davis
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
Zou, June X; Duan, Zhijian; Wang, Junjian et al. (2014) Kinesin family deregulation coordinated by bromodomain protein ANCCA and histone methyltransferase MLL for breast cancer cell growth, survival, and tamoxifen resistance. Mol Cancer Res 12:539-49
Duan, Zhijian; Zou, June X; Yang, Ping et al. (2013) Developmental and androgenic regulation of chromatin regulators EZH2 and ANCCA/ATAD2 in the prostate Via MLL histone methylase complex. Prostate 73:455-66
Kalashnikova, Ekaterina V; Revenko, Alexey S; Gemo, Abigael T et al. (2010) ANCCA/ATAD2 overexpression identifies breast cancer patients with poor prognosis, acting to drive proliferation and survival of triple-negative cells through control of B-Myb and EZH2. Cancer Res 70:9402-12
Hsia, Elaine Y; Goodson, Michael L; Zou, June X et al. (2010) Nuclear receptor coregulators as a new paradigm for therapeutic targeting. Adv Drug Deliv Rev 62:1227-37
Revenko, Alexey S; Kalashnikova, Ekaterina V; Gemo, Abigael T et al. (2010) Chromatin loading of E2F-MLL complex by cancer-associated coregulator ANCCA via reading a specific histone mark. Mol Cell Biol 30:5260-72
Zou, June X; Guo, Linlang; Revenko, Alexey S et al. (2009) Androgen-induced coactivator ANCCA mediates specific androgen receptor signaling in prostate cancer. Cancer Res 69:3339-46
Zou, June X; Revenko, Alexey S; Li, Li B et al. (2007) ANCCA, an estrogen-regulated AAA+ ATPase coactivator for ERalpha, is required for coregulator occupancy and chromatin modification. Proc Natl Acad Sci U S A 104:18067-72
Louie, Maggie C; Revenko, Alexey S; Zou, June X et al. (2006) Direct control of cell cycle gene expression by proto-oncogene product ACTR, and its autoregulation underlies its transforming activity. Mol Cell Biol 26:3810-23
Zou, June X; Zhong, Zhenyu; Shi, Xu-Bao et al. (2006) ACTR/AIB1/SRC-3 and androgen receptor control prostate cancer cell proliferation and tumor growth through direct control of cell cycle genes. Prostate 66:1474-86
Louie, Maggie C; Zou, June X; Rabinovich, Alina et al. (2004) ACTR/AIB1 functions as an E2F1 coactivator to promote breast cancer cell proliferation and antiestrogen resistance. Mol Cell Biol 24:5157-71

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