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 G(1)-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 alpha 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 G(1)-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 G(1)-phase progression by different classes of NRs.
Dipartimento di Patologia Generale, Seconda Università degli Studi di Napoli, 80138 Naples, Italy.
Luigi
L
Cicatiello
Raffaele
R
Addeo
Annarita
A
Sasso
Lucia
L
Altucci
Valeria Belsito
VB
Petrizzi
Raphaelle
R
Borgo
Massimo
M
Cancemi
Simona
S
Caporali
Silvana
S
Caristi
Claudio
C
Scafoglio
Diana
D
Teti
Francesco
F
Bresciani
Bruno
B
Perillo
Alessandro
A
Weisz
D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism*; D047628:Estrogen Receptor alpha; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D016193:G1 Phase / Q000502:physiology*; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006801:Humans; D046911:Macromolecular Substances; D008957:Models, Genetic; D011374:Progesterone / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism; D020218:Response Elements; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation
D047628:Estrogen Receptor alpha; D004967:Estrogens; D046911:Macromolecular Substances; D011518:Proto-Oncogene Proteins; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D011960:Receptors, Estrogen; D012097:Repressor Proteins; D014157:Transcription Factors; D019938:Cyclin D1; D011374:Progesterone