Minireview: Role of Kinases and Chromatin Remodeling in Progesterone Signaling to Chromatin

Abstract

Steroid hormones regulate gene expression by interaction of their receptors with hormone-responsive elements on DNA or with other transcription factors, but they can also activate cytoplasmic signaling cascades. Rapid activation of Erk by progestins via an interaction of the progesterone receptor (PR) with the estrogen receptor is critical for transcriptional activation of the mouse mammary tumor virus (MMTV) promoter and other progesterone target genes. Erk activation leads to the phosphorylation of PR, activation of mitogen- and stress-activated protein kinase 1, and the recruitment of a complex of the three activated proteins and of P300/CBP-associated factor (PCAF) to a single nucleosome, resulting in the phosphoacetylation of histone H3 and the displacement of heterochromatin protein 1γ. Hormone-dependent gene expression requires ATP-dependent chromatin remodeling complexes. Two switch/sucrose nonfermentable-like complexes, Brahma-related gene 1-associated factor (BAF) and polybromo-BAF are present in breast cancer cells, but only BAF is recruited to the MMTV promoter and cooperates with PCAF during activation of hormone-responsive promoters. PCAF acetylates histone H3 at K14, an epigenetic mark recognized by BAF subunits, thus anchoring the complex to chromatin. BAF catalyzes localized displacement of histones H2A and H2B, facilitating access of nuclear factor 1 and additional PR complexes to the hidden hormone-responsive elements on the MMTV promoter. The linker histone H1 is a structural component of chromatin generally regarded as a general repressor of transcription. However, it contributes to a better regulation of the MMTV promoter by favoring a more homogeneous nucleosome positioning, thus reducing basal transcription and actually enhancing hormone induced transcription. During transcriptional activation, H1 is phosphorylated and displaced from the promoter. The kinase cyclin-dependent kinase 2 is activated after progesterone treatment and could catalyze progesterone-induced phosphorylation of histone H1 by chromatin remodeling complexes. The initial steps of gene induction by progestins involve changes in the chromatin organization of target promoters that require the activation of several kinase signaling pathways initiated by membrane anchored PR. Because these pathways also respond to other external signals, they serve to integrate the hormonal response in the global context of the cellular environment.

Estrogen Receptor Alpha Mediates Progestin-Induced Mammary Tumor Growth by Interacting with Progesterone Receptors at the Cyclin D1/MYC Promoters

“…Ras /Erk, PI3K/Akt, and JAK/ STAT activation (7,8,42); conversely, model -ii-proposes that a polyproline motif in the amino-terminal domain of PR is sufficient to activate cell signaling pathways (9). Albeit a cytoplasmic as well as membrane localization of PR has been shown (21), we were not able to find PR colocalizing with ERa at these sites.…”

Progestin withdrawal at parturition in the mare

“…The functions of steroid hormone response elements are influenced by both genetic sequence and chromatin structure. However, the MMTV promoter in a useful for modeling the steroid hormone response (Adom et al 1991, Truss et al 1992, McNally et al 2000, Nagaich et al 2004, Vicent et al 2010, Wiench et al 2011. Chinese hamster ovarian (CHO) cells are not the ideal vehicle to explore the bioactivation of progesterone receptors by potential agonists, although even yeast-based assays have been utilized successfully and extensively (McRobb et al 2008).…”

Nucleosome Remodeling and Epigenetics

“…Nucleosome remodeling ATPases are involved in each and every aspect of genome utilization, be it the regulated execution of developmental gene expression programs (Chioda and Becker 2010;Ho and Crabtree 2010) or the fast transcriptional response to environmental signals (Vicent et al 2010). It also includes their involvement in the scheduled replication of the genome (Falbo and Shen 2006;Neves-Costa and Varga-Weisz 2006;Morettini et al 2008) or the surveillance of the genome for DNA damage and its repair by a range of strategies, including the recombination of chromosomal segments (Altaf et al 2007;Bao and Shen 2007;Downs et al 2007).…”