Steroid hormone receptors (SRs) are ligand-activated transcription factors and sensors for growth factor-initiated signaling pathways in hormonally regulated tissues, such as the breast or prostate. Recent discoveries suggest that several protein kinases are rapidly activated in response to steroid hormone binding to cytoplasmic SRs. Induction of rapid signaling upon SR ligand binding ensures that receptors and coregulators are appropriately phosphorylated as part of optimal transcription complexes. Alternatively, SR-activated kinase cascades provide additional avenues for SR-regulated gene expression independent of SR nuclear action. We provide an overview of SR and signaling cross talk in breast and prostate cancers, using the human progesterone receptor (PR) and androgen receptor (AR) as models. Kinases are emerging as key mediators of SR action. Cross talk between SR and membrane-initiated signaling events suggests a mechanism for coordinate regulation of gene subsets by mitogenic stimuli in hormonally responsive normal tissues; such cross talk is suspected to contribute to cancer biology.
"ith other regulatory proteins , changes in PR subcellular localization , or post - translational modifications ( e . g . , phosphorylation , ubiquitinylation , or sumoylation ) or other conditions that affect PR transcriptional activities , usually measured on artificial gene promoters ( reporter genes ) that contain one or more tandem PRE sites ( Lange et al . , 2007 ) . Growth factors , including EGF or heregulin , promote tran - scriptional synergy with progestins on PR - target genes ( Qiu and Lange , 2003 ; Daniel et al . , 2007b ; Shen et al . , 2001 ) . Phosphorylation events primarily serve to augment PR action in a promoter selective manner ( Daniel et al . , 2007a ) . Despite this depth of "
[Show abstract][Hide abstract] ABSTRACT: Progesterone is a member of a family of steroid hormones that act throughout the body to regulate homeostasis, development, reproduction, and behavior. Many of these biological effects of progesterone are mediated through the progestin receptor (PR), which is a member of the steroid/nuclear receptor superfamily of transcriptional activators. PR can act by a classic genomic mechanism that involves binding to DNA and transcription of target genes. Nuclear receptor coregulators are critical in modulating transcriptional activity of steroid receptors, including PR. Herein, we review recent findings from studies in cell lines and in brain on classic genomic mechanisms of PR action, including the function of nuclear receptor coregulators and chromatin remodeling. Recent studies indicate that PR can function at the membrane and can have rapid effects in the cytosol as mediators of growth factor-initiated signaling pathways. We have thus highlighted the importance of phosphorylation of PR by rapidly activated cytoplasmic protein kinases in breast cancer models and in brain and behavior. Integration of cytoplasmic signaling events with PR nuclear actions is predicted to have profound effects on PR action. The implications for these classic genomic and nongenomic signaling pathways on the biological functions of PR are discussed.
Hormones, Brain and Behavior, 3 edited by DW Pfaff, AP Arnold, AM Etgen, SE Fahrbach, R Rubin, 12/2009: chapter Molecular genomics of progestin actions: pages 1439-1465; Academic Press.
"In reality, most hormones initiate both rapid signaling events and transcriptional responses (DeWire et al., 2007; Lange et al., 2007). Nongenomic signaling events can occur with a slower time course, whereas rapid signaling events can stimulate pathways that directly or indirectly modulate gene expression (Fu and Simoncini, 2008; Ma and Pei, 2007). "
[Show abstract][Hide abstract] ABSTRACT: The effects of estrogen are widespread throughout the body. Although the classical nuclear estrogen receptors have been known for many years to decades and their primary modes of action as transcriptional regulators is well understood, certain aspects of estrogen biology remain inconsistent with the mechanisms of action of these receptor. More recently, the G protein-coupled receptor, GPR30/GPER, has been suggested to contribute to some of the cellular and physiological effects of estrogen. Not only does GPR30 mediate some of the rapid signal transduction events following cell stimulation, such as calcium mobilization and kinase activation, it also appears to regulate rapid transcriptional activation of genes such as c-fos. Since many cells and tissues co-express classical estrogen receptors and GPR30, there exists great diversity in the possible avenues of synergism and antagonism. In this review, we will provide an overview of GPR30 function, focusing on the rapid signaling events that culminate in the transcriptional activation of certain genes.
"Interestingly, PR expression is dramatically reduced in the bitransgenic mice. The literature suggests several mechanisms whereby these kinases may reduce PR transcription (Petz et al., 2004; Cui et al., 2003), or increase degradation of PR protein (Lange et al., 2007). Moreover, the combination of PRL with TGF-α can also cause mammary tumors in male mice, in contrast to the lack of tumors in single transgenic males (Arendt and Schuler, 2008b). "
[Show abstract][Hide abstract] ABSTRACT: The contributions of prolactin (PRL) to breast cancer are becoming increasingly recognized. To better understand the role for PRL in this disease, its interactions with other oncogenic growth factors and hormones must be characterized. Here, we review our current understanding of PRL crosstalk with other mammary oncogenic factors, including estrogen, epidermal growth factor (EGF) family members, and insulin-like growth factor-I (IGF-I). The ability of PRL to potentiate the actions of these targets of highly successful endocrine and molecular therapies suggests that PRL and/or its receptor (PRLR) may be an attractive therapeutic target(s). We discuss the potential benefit of PRL/PRLR-targeted therapy in combination with established therapies and implications for de novo and acquired resistance to treatment.
Kazuharu Kai, Kimie Kondo, Xiaoping Wang, Xuemei Xie, Mary Kathryn Pitner, Monica E Reyes, Angie M Torres-Adorno, Hiroko Masuda, Gabriel N Hortobagyi, Chandra Bartholomeusz, Hideyuki Saya, Debu Tripathy, Subrata Sen, Naoto T Ueno
Goar Sánchez-Sanz, David Matallanas, Lan K Nguyen, Boris N Kholodenko, Edina Rosta, Walter Kolch, Nicolae-Viorel Buchete
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