PELP1 - A Key Mediator of Estrogen Signaling and Actions in the Brain

Abstract

Proline-, Glutamic acid-, and Leucine-rich Protein 1 (PELP1) is an estrogen receptor (ER) coregulator protein identified by our collaborative group. Work from our lab and others has shown that PELP1 is a scaffold protein that interacts with ERs, kinase signaling factors, as well as proteins involved in chromatin remodeling and DNA repair. Its role in mediating 17β-Estradiol (E2) signaling and actions has been heavily studied in cancer cells, but only recently has attention turned to its role in the brain. In this review, we discuss the tissue, cellular and subcellular localization of PELP1 in the brain. We also discuss recent evidence from PELP1 forebrain-specific knockout mice that demonstrate a critical role of PELP1 in mediating both extranuclear and nuclear ER signaling in the brain, as well as E2-induced neuroprotection, anti-inflammatory effects, and regulation of cognitive function. Finally, the PELP1 interactome and unique gene network regulated by PELP1 in the brain is discussed, especially as it provides new insights into PELP1 biology, protein interactions, and mechanisms of action in the brain. As a whole, the findings discussed in this review indicate that PELP1 functions as a critical ER coregulator in the brain to mediate E2 signaling and actions.

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