Progesterone Signaling to Chromatin in Breast Cancer Cells. Two Initial Cycles of Remodeling

Abstract

Steroid hormones control gene activity by direct interaction of their intracellular receptors with hormone responsive elements on DNA but they can also crosstalk to kinase cascades activated by signals impinging on membrane receptors. Progesterone treatment of cells in culture leads to the rapid activation of several kinases and in particular the Src/Ras/Erk/Msk1 cascade, by activating a small population of membrane-anchored progesterone receptors (PR). One to five minutes after hormone treatment, activated Erk enters the nucleus and causes the recruitment of the activated ternary complex of pPR, pERK and pMSK1 to target chromatin, leading to phosphoacetylation of histone H3 and displacement of an HP1$\tilde{\gamma}$ containing repressive complex. Thus, progestin activation of the Src/Ras/Erk/Msk1 cascade directly impacts chromatin. Within one minute of adding synthetic progesterone analogues to breast cancer cells, PR recruits to the target genes an ATP-dependent chromatin remodeling complex, NURF, a histone methyltransferase complex, ASCOM, which trimethylates histone H3 at lysine 4, and an activated Cyclin A/CDK2 complex, that phosphorylates histone H1 and facilitates its displacement. This first cycle of chromatin remodeling is a prerequisite for a second cycle starting 5 min after hormone addition, in which a different ATP-dependent chromatin remodeling complex, BAF, and a histone acetyltransferase, PCAF, cooperate to promote the displacement of core histones H2A and H2B, that facilitates access to the promoter of additional receptor complexes and other transcription factors necessary for gene induction. Thus, at both phases in activation of target promoters, a histone tail modification stabilizes the binding of an ATP-dependent chromatin remodeler to target promoters. These findings highlight the concept of transcription initiation as a process involving consecutive cycles of enzymatic chromatin remodeling, where each enzyme complex is necessary at a given time point and catalyzes a particular remodeling step.