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

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 re- ceptor (PR), SWI/SNF, and SNF2h-related complexes to MMTV pro- moter. 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 re- modeling 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 estro- gen 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 HP1� , and recruitment of Brg1, PCAF, and RNA polymerase II. Block- ing 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 ERthat activates the Erk and Akt kinase path- ways leading to cell proliferation in the absence of direct transcriptional