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

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 (ER alpha) has been known to be a major mediator of cellular estrogenic signaling. Accumulating evidence has shown that the regulations of ER alpha gene transcription, splicing, and expression across the tissues are highly complex. The ER alpha promoter region is composed of multiple leader exons and 5 '-untranslated region (5 '-UTR) exons. Differential splicing results in multiple ER alpha proteins with different molecular weights and functional domains. Furthermore, various post-translational modifications (PTMs) further impact ER alpha cellular localization, ligand affinity, and therefore functionality. These splicing isoforms and PTMs are differentially expressed in a tissue-specific manner, mediate certain aspects of ER alpha signaling, and may work even antagonistically against the full-length ER alpha. The fundamental understanding of the ER alpha 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 ER alpha variants and the PTMs in normal physiological processes, particularly as studied in transgenic mouse models.