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

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 controlled by ovarian steroids through mechanism(s) not fully elucidated. We describe here that CCND1 promoter activation by estrogens in human breast cancer (hBC) cells is mediated by recruitment of the c-Jun/c-Fos/ER? complex to the TRE of the gene, together with Oct-1 to a site immediately adjacent. This coincides with the release from the same DNA region of a transcriptional repressor complex including YY1 and HDAC1 and is sufficient to induce assembly of the basal transcription machinery on the promoter and to lead to initial cyclin D1 accumulation in the cell. Later on into estrogen stimulation, the cyclin D1/Cdk4 holoenzyme associates to the CCND1 gene promoter via a pre-bound E2F/pRb complex, achieving the longer- 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 uncovered here represents a cross-road for transcriptional control of G1 phase progression by different classes of NRs.