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Molecular and Cellular Biology, August 2004, p. 7260-7274, Vol. 24, No. 16
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.16.7260-7274.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Estrogens and Progesterone Promote Persistent CCND1 Gene Activation during G₁ by Inducing Transcriptional Derepression via c-Jun/c-Fos/Estrogen Receptor (Progesterone Receptor) Complex Assembly to a Distal Regulatory Element and Recruitment of Cyclin D1 to Its Own Gene Promoter

Luigi Cicatiello,^1, Raffaele Addeo,^1, Annarita Sasso,¹ Lucia Altucci,¹ Valeria Belsito Petrizzi,¹ Raphaelle Borgo,¹ Massimo Cancemi,¹ Simona Caporali,¹ Silvana Caristi,^1,2 Claudio Scafoglio,¹ Diana Teti,² Francesco Bresciani,¹ Bruno Perillo,³ and Alessandro Weisz^1*

Dipartimento di Patologia Generale, Seconda Università degli Studi di Napoli, 80138 Naples,¹ Dipartimento di Patologia e Microbiologia Sperimentale, Università degli Studi di Messina, 98125 Messina,² Istituto di Scienze dell'Alimentazione-C.N.R., 83100 Avellino, Italy³

Received 7 January 2004/ Returned for modification 10 February 2004/ Accepted 20 May 2004

Transcriptional activation of the cyclin D1 gene (CCND1) plays a pivotal role in G₁-phase progression, which is thereby controlled by multiple regulatory factors, including nuclear receptors (NRs). Appropriate CCND1 gene activity is essential for normal development and physiology of the mammary gland, where it is regulated by ovarian steroids through a mechanism(s) that is not fully elucidated. We report here that CCND1 promoter activation by estrogens in human breast cancer cells is mediated by recruitment of a c-Jun/c-Fos/estrogen receptor complex to the tetradecanoyl phorbol acetate-responsive element of the gene, together with Oct-1 to a site immediately adjacent. This process coincides with the release from the same DNA region of a transcriptional repressor complex including Yin-Yang 1 (YY1) and histone deacetylase 1 and is sufficient to induce the assembly of the basal transcription machinery on the promoter and to lead to initial cyclin D1 accumulation in the cell. Later on in estrogen stimulation, the cyclin D1/Cdk4 holoenzyme associates with the CCND1 promoter, where E2F and pRb can also be found, contributing to the long-lasting gene enhancement required to drive G₁-phase completion. Interestingly, progesterone triggers similar regulatory events through its own NRs, suggesting that the gene regulation cascade described here represents a crossroad for the transcriptional control of G₁-phase progression by different classes of NRs.

L.C. and R.A. contributed equally to this work and therefore should be considered equal first authors.

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