Estrogens play key roles in development and maintenance of normal reproductive function. In both men and women estrogens are important in the functioning of the cardiovascular, musculoskeletal, immune, and central nervous systems.Cellular signaling of estrogens is mediated through two estrogen receptors (ERs), ERα and ERβ which belong to the nuclear receptor family of transcription factors. ERβ antagonizes ERα signaling by competing for estrogen and DNA binding sites. Estrogen signaling is thus a balance between the effects of the two receptors. Emerging evidence suggests that there are several pathways by which estrogens and ERs regulate biological processes. Ligand-dependent activation triggers recruitment of a variety of coregulators to ER to form a complex that positively or negatively regulates transcription by the RNA polymerase II (Pol II) machinery.
The best-defined structure-function coregulator interaction of ERα is with the steroid receptor coactivator SRC (p160) family of coactivators. Amongst the other coactivators are, glucocorticoid receptor interacting protein 1 (GRIP1), CREB binding protein (CBP/p300), thyroid hormone receptor-associated protein complex component (TRAP220), PPAR gamma coactivator-1(PGC-1), DEAD box RNA helicase (DDX5) and steroid receptor RNA activator (SRA). Several corepressors regulate the activity of ERα either directly or via inhibiting a coactivator. Examples of direct inhibition include receptor interacting protein (RIP140), silencing mediator of retinoid and thyroid receptors (SMRT) and progesterone receptor (PGR). Corepressors of ER that inhibit indirectly include nuclear receptor corepressor (N-CoR1) and SMRT/HDAC1 associated repressor protein (SHARP). Some of the genes whose expression is enhanced as a result of ERα signaling include phosphoenolpyruvate carboxykinase (PEPCK), glucose 6 phosphatase and insulin-like growth factor binding protein-1 (IGFBP1).
The ligand-induced activation of ERα leads to non-genomic effects in addition to genomic effects.The activation of ERα by proline, glutamate and leucine-rich protein 1(PELP1) triggers the RAS/extracellular signal related kinase (ERK) pathway via SRC kinase activation. ERK in turn phosphorylates ERα in the nucleus, resulting in enhancement of function. In addition ERα in response to estrogen can directly activate the SH domain containing adapter protein (SHC) resulting in triggering the RAS/ERK pathway. (Upgraded 01/2020)