Chromatin Remodeling and Control of Cell Proliferation by Progestins via Cross Talk of Progesterone Receptor with the Estrogen Receptors and Kinase Signaling Pathways

Abstract

Transcription from the mouse mammary tumor virus (MMTV) promoter can be induced by glucocorticoids or progestins. Progesterone treatment of cultured cells carrying an integrated single copy of an MMTV transgene leads to recruitment of progesterone receptor (PR), SWI/SNF, and SNF2h-related complexes to MMTV promoter. Recruitment is accompanied by selective displacement of histones H2A and H2B from the nucleosome B. In nucleosomes assembled on promoter sequences, SWI/SNF displaces histones H2A and H2B from MMTV nucleosome B, but not from other MMTV nucleosomes or from an rDNA promoter nucleosome. Thus, the outcome of nucleosome remodeling by purified SWI/SNF depends on the DNA sequence. On the other hand, 5 min after hormone treatment, the cytoplasmic signaling cascade Src/Ras/Erk is activated via an interaction of PR with the estrogen receptor, which activates Src. As a consequence of Erk activation PR is phosphorylated, Msk1 is activated, and a ternary complex PR-Erk-Msk1 is recruited to MMTV nucleosome B. Msk1 phosphorylates H3 at serine 10, which is followed by acetylation at lysine 14, displacement of HP1gamma, and recruitment of Brg1, PCAF, and RNA polymerase II. Blocking Erk activation or Msk1 activity prevents induction of the MMTV transgene. Thus, the rapid nongenomic effects of progestins are essential for their transcriptional effects on certain progestin target genes. In rat endometrial stromal cells, picomolar concentrations of progestins trigger the cross talk of PR with ERbeta that activates the Erk and Akt kinase pathways leading to cell proliferation in the absence of direct transcriptional effects of the ligand-activated PR. Thus, depending on the cellular context rapid kinase activation and transcriptional effect play different roles in the physiological response to progestins.

Progesterone Induction of the 11β-Hydroxysteroid Dehydrogenase Type 2 Promoter in Breast Cancer Cells Involves Coordinated Recruitment of STAT5A and Progesterone Receptor to a Distal Enhancer and Polymerase Tracking

“…The MMTV promoter contained in its 5Ј long terminal repeat has been extensively studied and has become the model for progesterone-and glucocorticoid-induced gene expression in human breast cancer cell lines (17,63). Using this model, we have recently contributed to connecting the rapid signaling activation by progesterone with its transcriptional effect (62).…”

Thermodynamic Dissection of Progesterone Receptor Interactions at the Mouse Mammary Tumor Virus Promoter: Monomer Binding and Strong Cooperativity Dominate the Assembly Reaction

“…Semiquantitative footprinting and filter binding studies indicated that receptors bound at all four of the PREs, [2][3][4] and glycerol gradient centrifugation studies 4 suggested that dimers assembled at each site. 5 Finally, mutational studies indicated that loss of any one site decreased the level of transcriptional activity up to 10-fold, 6 demonstrating that transcriptional activation was synergistic in character and, thus, suggestive of communication among the sites.…”

Four enzymes cooperate to displace histone H1 during the first minute of hormonal gene activation

“…Initial studies focused on the role of histone acetylation and, to a lesser extent, on histone phosphorylation and histone arginine methylation (Bartsch et al 1996;Spencer et al 1997;Li et al 2003;Metivier et al 2003;Vicent et al 2006b), while lysine methylation has not been studied extensively (Metzger et al 2005;Wissmann et al 2007). Although H3 trimethylated at Lys 4 (H3K4me3) is associated with transcription start sites (TSSs) of active genes (Santos-Rosa et al 2002, 2003Schneider et al 2004), the role of this modification during mouse mammary tumor virus (MMTV) activation has been questioned (Kinyamu and Archer 2007).…”