Estrogen Receptor Alpha Splice Variants, Post-Translational Modifications, and Their Physiological Functions

• Published in: Cells (Basel, Switzerland) Vol. 12; no. 6; p. 895
• Main Authors: Saito, Kenji, Cui, Huxing
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 01.03.2023; MDPI
• Subjects: 5' Untranslated Regions; Alternative splicing; Alternative Splicing - genetics; Amino acids; Analysis; Animal models; Animals; Breast cancer; Energy metabolism; estrogen receptor alpha; Estrogen Receptor alpha - genetics; Estrogen Receptor alpha - metabolism; Estrogen receptors; Estrogens; Exons; G proteins; Genetic engineering; Hormones; Hormones, Sex; Isoforms; Ligands; Localization; Methods; Mice; mutant mouse models; Ovaries; Physiology; Post-translation; Post-translational modification; post-translational modifications; Protein Isoforms - genetics; Protein Isoforms - metabolism; Protein Processing, Post-Translational - physiology; Proteins; Review; splicing isoforms; Steroids; Transcription factors; Transgenic mice; Translation; Uterus; Xenoestrogens; United States; mutant mouse models; splicing isoforms; post-translational modifications; estrogen receptor alpha
• ISSN: 2073-4409; 2073-4409
• DOI: 10.3390/cells12060895

The importance of estrogenic signaling for a broad spectrum of biological processes, including reproduction, cancer development, energy metabolism, memory and learning, and so on, has been well documented. Among reported estrogen receptors, estrogen receptor alpha (ERα) has been known to be a major mediator of cellular estrogenic signaling. Accumulating evidence has shown that the regulations of ERα gene transcription, splicing, and expression across the tissues are highly complex. The ERα promoter region is composed of multiple leader exons and 5'-untranslated region (5'-UTR) exons. Differential splicing results in multiple ERα proteins with different molecular weights and functional domains. Furthermore, various post-translational modifications (PTMs) further impact ERα cellular localization, ligand affinity, and therefore functionality. These splicing isoforms and PTMs are differentially expressed in a tissue-specific manner, mediate certain aspects of ERα signaling, and may work even antagonistically against the full-length ERα. The fundamental understanding of the ERα splicing isoforms in normal physiology is limited and association studies of the splicing isoforms and the PTMs are scarce. This review aims to summarize the functional diversity of these ERα variants and the PTMs in normal physiological processes, particularly as studied in transgenic mouse models.