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The breast cell growth inhibitor, estrogen down regulated gene 1, modulates a novel functional interaction between estrogen receptor alpha and transcriptional elongation factor cyclin T1

Oncogene volume 24, pages 5576–5588 (2005)Cite this article

Abstract

Estrogen receptor alpha (ERα) regulates transcription of specific genes and is believed to play a major role in breast tumorigenesis. We previously identified estrogen down regulated gene 1 (EDG1 (also known as HEXIM1)) using the C-terminus of ERα (E/F domain) as bait in yeast two-hybrid screenings. Here we report on the role of EDG1 as a coregulator of ERα transcriptional activity. We observe an interaction between EDG1 and ERα. EDG1 inhibits the transcriptional activity of ERα and this is dependent upon the C-terminus of EDG1. The C-terminus of EDG1/HEXIM1 was recently shown to inhibit the positive transcription elongation factor b (P-TEFb) by interacting with the cyclin T1 subunit. Here we show that ERα interacts with cyclin T1, cyclin T1 and ER co-occupancy on the promoter region of an ER target gene, and that this interaction plays an important role in ERα-induced gene expression. The interaction of ERα with cyclin T1 also allows ERα to compete with EDG1 for cyclin T1, and may release cyclin T1 from EDG1 repression. Conversely, increased EDG1 expression results in inhibition of cyclin T1 recruitment and ERα DNA binding. Our results support a novel functional interaction between ERα and cyclin T1 that is modulated by EDG1.

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Abbreviations

CLP-1:

cardiac lineage protein 1

ERα:

estrogen receptor α

E2:

17β-estradiol

TOT:

trans-hydroxytamoxifen

EDG1:

estrogen down regulated gene 1

HEXIM1:

hexamethylene-bis-acetamide-inducible protein 1

P-TEFb:

positive transcription elongation factor b

RNAP II:

RNA polymerase II

CTD:

carboxy terminal domain

ERE:

estrogen receptor response element

ChIP:

chromatin immunoprecipitation

NLS:

nuclear localization signal

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Acknowledgements

We are grateful to Laura Chaplin, Yehong Huang, Michael Zane, and Abigail Ratcheson for technical assistance. This work was supported by Grant CA92440 from the National Institute of Health to MMM and Grant IRG-91-022-09 from the American Cancer Society to KF.

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Authors and Affiliations

  1. Department of Pharmacology, Case Western Reserve University, Cleveland, 44106, OH, USA

    Bryan M Wittmann, Huayun Deng, Ndiya Ogba & Monica M Montano

  2. Department of Molecular Biology and Microbiology, Case Western Reserve University, Cleveland, 44106, OH, USA

    Koh Fujinaga

  3. Division of Infectious Diseases, Case Western Reserve University, Cleveland, 44106, OH, USA

    Koh Fujinaga

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  1. Bryan M Wittmann
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Correspondence to Monica M Montano.

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Wittmann, B., Fujinaga, K., Deng, H. et al. The breast cell growth inhibitor, estrogen down regulated gene 1, modulates a novel functional interaction between estrogen receptor alpha and transcriptional elongation factor cyclin T1. Oncogene 24, 5576–5588 (2005). https://doi.org/10.1038/sj.onc.1208728

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