期刊
CANCER RESEARCH
卷 73, 期 14, 页码 4488-4499出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-12-4078
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资金
- NIH [RO1CA132115, R01CA70896, R01CA75503, R01CA86072, P30CA56036]
- Dr. Ralph and Marian C. Falk Medical Research Trust
- Breast Cancer Research Foundation
- Margaret Q. Landenberger Research Foundation
- Department of Defense Concept Award [W81XWH-11-1-0303]
The Drosophila Eyes Absent Homologue 1 (EYA1) is a component of the retinal determination gene network and serves as an H2AX phosphatase. The cyclin D1 gene encodes the regulatory subunits of a holoenzyme that phosphorylates and inactivates the pRb protein. Herein, comparison with normal breast showed that EYA1 is overexpressed with cyclin D1 in luminal B breast cancer subtype. EYA1 enhanced breast tumor growth in mice in vivo, requiring the phosphatase domain. EYA1 enhanced cellular proliferation, inhibited apoptosis, and induced contact-independent growth and cyclin D1 abundance. The induction of cellular proliferation and cyclin D1 abundance, but not apoptosis, was dependent upon the EYA1 phosphatase domain. The EYA1-mediated transcriptional induction of cyclin D1 occurred via the AP-1-binding site at 953 and required the EYA1 phosphatase function. The AP-1 mutation did not affect SIX1-dependent activation of cyclin D1. EYA1 was recruited in the context of local chromatin to the cyclin D1 AP-1 site. The EYA1 phosphatase function determined the recruitment of CBP, RNA polymerase II, and acetylation of H3K9 at the cyclin D1 gene AP-1 site regulatory region in the context of local chromatin. The EYA1 phosphatase regulates cell-cycle control via transcriptional complex formation at the cyclin D1 promoter. (C) 2013 AACR.
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