PGRMC1 (progesterone receptor membrane component 1): A targetable protein with multiple functions in steroid signaling, P450 activation and drug binding

Abstract

Summary Hormone signaling is important in a number of disease states, and hormone receptors are effective therapeutic targets. PGRMC1 (progesterone receptor membrane component 1) is a member of a multi-protein complex that binds to progesterone and other steroids, as well as pharmaceutical compounds. In spite of its name, PGRMC1 shares homology with cytochrome b5-related proteins rather than hormone receptors, and heme binding is the sole biochemical activity of PGRMC1. PGRMC1 and its homologues regulate cholesterol synthesis by activating the P450 protein Cyp51/lanosterol demethylase, and the cholesterol synthetic pathway is an important target in cardiovascular disease and in treating infections. PGRMC1 binding partners include multiple P450 proteins, PAIR-BP1, Insig, and an uncharacterized hormone/drug-binding protein. PGRMC1 is induced in a spectrum of cancers, where it promotes cell survival and damage resistance, and PGRMC1 is also expressed in the nervous system and tissues involved in drug metabolism, cholesterol synthesis and hormone synthesis and turnover. One of the appealing features of PGRMC1 and its associated protein complex is its affinity for steroids and drugs. Together with its biological role in promoting tumor survival, PGRMC1 is an attractive target for therapeutic intervention in cancer and related malignancies.

Involvement of let-7/miR-98 microRNAs in the regulation of progesterone receptor membrane component 1 expression in ovarian cancer cells

“…Additionally, these results show that the prediction of miRNA binding sites in a certain target by software programs definitely must be confirmed by experimental approaches. Finally, our in vitro studies support previous studies, which show that P4 regulates PGRMC1 mRNA levels (7,13,14,33). However, the effect of P4 on PGRMC1 expression seems to be tissue specific, since a downregulation of PGRMC1 by P4 was detected in some tissues, while an upregulation was shown in others (7).…”

“…Finally, our in vitro studies support previous studies, which show that P4 regulates PGRMC1 mRNA levels (7,13,14,33). However, the effect of P4 on PGRMC1 expression seems to be tissue specific, since a downregulation of PGRMC1 by P4 was detected in some tissues, while an upregulation was shown in others (7). For example, in secretory endometrium of rhesus monkeys P4 downregulates PGRMC1 mRNA levels (13).…”

Molecular evolution of the membrane associated progesterone receptor in the Brachionus plicatilis (Rotifera, Monogononta) species complex

“…3). Rohe et al (2009) reviewed four sites required for heme binding in the homolog PGRMC1 surrounding a putative ligand-binding cleft, which we found were identical to those in rotifers at analogous sites (Fig. 3).…”

“…Four residues critical for heme binding in PGRMC1 are conserved in rotifers. It has been proposed structural elements required for binding heme also function in interactions with a binding partner that mediates progesterone signaling (Rohe et al, 2009), though study is needed to clarify roles of specific amino acids in a progesterone pathway. In rotifers, most substitutions in the heme/steroid binding domain are distal to the ligand-binding cleft and are conservative or moderately conservative.…”

“…The MAPR gene family is proposed to have originated from an ancestral cytochrome b5 (Cyt b5), and contains Neudesin and the vertebrate-specific paralogs progesterone receptor membrane component (PGRMC) 1 and 2 (Cahill, 2007). Functions of MAPR proteins vary across phyla and range from inhibition of apoptosis in ovarian granulosa cells to cholesterol synthesis and axon guidance (Cahill, 2007;Rohe et al, 2009). While progesterone binding cannot be assumed by homology, it is notable that the Brachionus putative MAPR is the only known candidate receptor for progesterone.…”