PGRMC1
Protein-coding gene in the species Homo sapiens From Wikipedia, the free encyclopedia
Protein-coding gene in the species Homo sapiens From Wikipedia, the free encyclopedia
Progesterone receptor membrane component 1 (abbreviated PGRMC1) is a protein which co-purifies with progesterone binding proteins in the liver and ovary.[5][6] In humans, the PGRMC1 protein is encoded by the PGRMC1 gene.[7]
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Aliases | PGRMC1, HPR6.6, MPR, progesterone receptor membrane component 1, Dap1, IZA, 25-Dx | ||||||||||||||||||||||||||||||||||||||||||||||||||
External IDs | OMIM: 300435; MGI: 1858305; HomoloGene: 48457; GeneCards: PGRMC1; OMA:PGRMC1 - orthologs | ||||||||||||||||||||||||||||||||||||||||||||||||||
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The sole biochemical function of PGRMC1 is heme-binding.[8][9] PGRMC1 shares key structural motifs with cytochrome b5.[10] PGRMC1 binds and activates P450 proteins,[11][12][13] which are important in drug, hormone and lipid metabolism. PGRMC1 also binds to PAIR-BP1 (plasminogen activator inhibitor RNA-binding protein-1).[6] However, its expression outside of the reproductive tract and in males suggests multiple functions for the protein. These may include binding to Insig (insulin-induced gene),[14] which regulates cholesterol synthesis.[15]
PGRMC1 is highly expressed in the liver and kidney in humans[7] with lower expression in the brain, lung, heart, skeletal muscle and pancreas.[7][16][17] In rodents, PGRMC1 is found in the liver, lung, kidney and brain.[16][17] PGRMC1 is over-expressed in breast tumors and in cancer cell lines from the colon, thyroid, ovary, lung, and cervix.[18][19] Microarray analyses have detected PGRMC1 expression in colon, lung and breast tumors.[20][21][22]
PGRMC1 expression is induced by the non-genotoxic carcinogen 2,3,7,8-tetrachlorodibenzo-p-dioxin in the rat liver,[17] but this induction is specific to males.[23] PGRMC1 is expressed in the ovary and corpus luteum, where its expression is induced by progesterone[24] and during pregnancy,[25] respectively. PGRMC1 is expressed in various regions of the brain (hypothalamic area, circumventricular organs, ependymal cells of the lateral ventricles, meninges),[16][26] including regions known to facilitate lordosis.[16]
The PGRMC1 yeast homologue, Dap1 (damage associated protein 1), binds heme[9][27] through a penta-coordinate mechanism.[9][28] Yeast cells lacking the DAP1 gene are sensitive to DNA damage,[29] and heme-binding is essential for damage resistance.[27] Dap1 is also required for a critical step in cholesterol synthesis in which the P450 protein Erg11/Cyp51 removes a methyl group from lanosterol.[11][27][29][30] Erg11/Cyp51 is the target of the azole antifungal drugs. As a result, yeast cells lacking the DAP1 gene are highly sensitive to antifungal drugs[11][27][29] This function is conserved between the unrelated fungi S. cerevisiae and S. pombe. Dap1 also regulates the metabolism of iron in yeast.[30]
In yeast and humans, PGRMC1 binds directly to P450 proteins, including CYP51A1, CYP3A4, CYP7A1 and CYP21A2.[11] PGRMC1 also activates Cyp21 when the two proteins are co-expressed,[12][13] indicating that PGRMC1 promotes progesterone turnover. Just as Dap1 is required for the action of Erg11 in the synthesis of ergosterol in yeast, PGRMC1 regulates the Cyp51-catalyzed demethylation step in human cholesterol synthesis.[11] Thus, PGRMC1 and its homologues bind and regulate P450 proteins, and it has been likened to “a helping hand for P450 proteins”.[31]
The yeast PGRMC1 homologue is required for resistance to damage.[29] PGRMC1 also promotes survival in human cancer cells after treatment with chemotherapy.[6][8] In contrast, PGRMC1 promotes cell death in cancer cells after oxidative damage.[32] PGRMC1 alters several known survival signaling proteins, including the Akt protein kinase and the cell death-associated protein IκB.[32] Progesterone inhibits apoptosis in immortalized granulosa cells, and this activity requires PGRMC1 and its binding partner, PAIR-BP1 (plasminogen activator inhibitor RNA-binding protein-1).[6] However, PAIR-BP1 is not a progesterone binding protein, and the component of the PGRMC1 complex that binds to progesterone is unknown.
PGRMC1 was originally thought to represent a progesterone receptor of some sort and to bind to progesterone, but subsequently thought has moved towards PGRMC1 acting as a downstream mediator of some other progesterone-binding protein.[33]
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