Affinage

PGRMC1

Membrane-associated progesterone receptor component 1 · UniProt O00264

Length
195 aa
Mass
21.7 kDa
Annotated
2026-06-10
100 papers in source corpus 30 papers cited in narrative 29 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 9/9 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PGRMC1 is a heme-binding cytochrome b5-related membrane protein that functions as a multivalent scaffold coupling heme chemistry to protein stabilization, organelle quality control, and growth signaling (PMID:18992768, PMID:27599036). Its cytosolic domain coordinates heme via an axial tyrosinate (Y95/Y113) in a five-coordinate high-spin configuration and uses the two protruding heme groups to form stacking dimers; CO binding to the vacant sixth coordination site disrupts dimerization, and this heme-mediated dimerization is required for productive interactions with EGFR and cytochromes P450 (PMID:26988023, PMID:25675345). Through these interactions PGRMC1 stabilizes a broad range of cytochromes P450 post-transcriptionally and in a heme-independent manner, raises plasma-membrane EGFR levels, and regulates cellular sensitivity to EGFR-targeted drugs (PMID:34678314, PMID:20538600). PGRMC1 also engages the terminal heme-biosynthetic enzyme ferrochelatase—an interaction that requires Y113 axial coordination—modulating ferrochelatase activity and acting as a heme donor to apo-cytochrome b5, thereby placing it at the interface of heme production and distribution (PMID:27599036, PMID:34678314). In the ER lumen, PGRMC1 serves as a size-selective cargo receptor that recognizes misfolded prohormones such as mutant proinsulin and POMC and routes small oligomers for RTN3-dependent ER-phagy (PMID:34645803, PMID:34779709). PGRMC1 transduces progesterone responses chiefly by chaperoning membrane progesterone receptor alpha (mPRα) to the cell surface, an activity confirmed in vivo where Pgrmc1 loss reduces mPRα and impairs oocyte maturation (PMID:24424068, PMID:30319543). Additional outputs include progesterone-induced SUMOylation that suppresses Tcf/Lef transcription (PMID:22719051), promotion of store-operated Ca2+ entry through direct binding to the STIM1 coiled-coil (PMID:35045297), and ER-stress-independent activation of PERK to phosphorylate eIF2α and block c-Myc translation (PMID:39747098). PGRMC1 activity is governed by phosphorylation at multiple sites (S57, Y180, S181), which control dimerization, partner interactions including prohibitin binding, and tumorigenic capacity (PMID:32245408, PMID:34830790). A disease-associated H165R missense mutation in the cytochrome b5 domain, linked to premature ovarian failure, abolishes CYP7A1 binding and attenuates progesterone's anti-apoptotic action (PMID:18782852).

Mechanistic history

Synthesis pass · year-by-year structured walk · 28 steps
  1. 2003 Low

    Established an early functional readout linking PGRMC1 expression to a non-canonical oxidative-stress death pathway in breast cancer cells, before its biochemistry was known.

    Evidence HPR6.6/PGRMC1 overexpression with H2O2 challenge and Akt/IκB inhibitor exclusion in MCF-7 cells

    PMID:14523988

    Open questions at the time
    • Pathway defined only by exclusion of Akt/IκB
    • No molecular mechanism for the death signal
    • Single overexpression system
  2. 2007 Medium

    Tested whether PGRMC1 itself binds progesterone and mediates progesterone's antiapoptotic action, addressing whether it is a direct steroid sensor.

    Evidence [3H]progesterone binding with GFP-PGRMC1 fusion, deletion mutagenesis, and siRNA in granulosa cells

    PMID:17991724

    Open questions at the time
    • Did not resolve whether binding is direct vs. via partners
    • Structural basis of binding unknown
    • PAIRBP1 contribution not separated
  3. 2008 Medium

    Defined PGRMC1's core biochemical identity as a heme-binding, cytochrome b5-related protein that activates P450 enzymes, framing it as a P450-coupling factor.

    Evidence Biochemical binding and enzymatic activity assays (review-level synthesis) implicating CYP51, PAIR-BP1, Insig

    PMID:18992768

    Open questions at the time
    • Primary data are review-level
    • Heme coordination geometry not defined here
    • Mechanism of P450 activation unresolved
  4. 2008 Medium

    Showed phosphorylation regulates PGRMC1's stress function, introducing post-translational control as a determinant of activity.

    Evidence 2D-PAGE phosphoproteomics and S56/S180 mutagenesis with peroxide-survival assays in MCF7 tumors and cells

    PMID:18922159

    Open questions at the time
    • Kinases responsible not identified
    • Link between phospho-state and molecular interactions not yet mapped
  5. 2008 Medium

    Connected a PGRMC1 missense mutation to premature ovarian failure and to loss of a specific P450 interaction, providing the first human disease link.

    Evidence H165R mutation screening with CYP7A1-binding and progesterone anti-apoptosis assays in ovarian cells

    PMID:18782852

    Open questions at the time
    • Causality vs. association not fully established
    • Effect on other P450 partners untested
  6. 2010 Medium

    Defined PGRMC1 as an EGFR-stabilizing partner that raises plasma-membrane EGFR and modulates EGFR-inhibitor sensitivity, linking it to growth-factor signaling.

    Evidence Reciprocal co-IP, fractionation, immunofluorescence, and EGFR inhibitor viability assays

    PMID:20538600

    Open questions at the time
    • Whether binding is direct not established
    • Mechanism of EGFR stabilization unresolved
  7. 2011 Medium

    Identified PGRMC1 as the protein labeled by a sigma-2 photoaffinity probe, an assignment later partly reassigned.

    Evidence Photoaffinity labeling, MS identification, and gain/loss-of-function radioligand binding in HeLa cells

    PMID:21730960

    Open questions at the time
    • Sigma-2 identity later contested (see 2018)
    • Functional consequence of sigma-2 ligand binding unclear
  8. 2012 Medium

    Showed progesterone drives PGRMC1 SUMOylation and nuclear localization to suppress Tcf/Lef transcription, revealing a transcriptional output.

    Evidence Co-IP/PLA with SUMO-1, nuclear fractionation, Tcf/Lef reporter, and SUMO-site mutagenesis

    PMID:22719051

    Open questions at the time
    • SUMO E3 ligase not identified
    • Direct DNA/transcription-machinery contacts unknown
  9. 2012 Medium

    Placed Pgrmc1 upstream of ERK5 in progesterone-induced BDNF release from glia, extending its signaling role to the nervous system.

    Evidence siRNA knockdown with BDNF measurement and ERK5 vs. ERK1/2 inhibition in glial cells/astrocytes

    PMID:22778217

    Open questions at the time
    • Receptor coupling to ERK5 not defined
    • Whether mPRα participates not tested
  10. 2014 Medium

    Reframed PGRMC1's progesterone signaling as adaptor-mediated, showing it traffics mPRα to the cell surface and that antiapoptotic effects require mPRα.

    Evidence Stable overexpression, [3H]progesterone binding, co-IP, and mPRα siRNA epistasis

    PMID:24424068

    Open questions at the time
    • Direct PGRMC1-mPRα binding interface unmapped
    • Reconciliation with direct-progesterone-binding model incomplete
  11. 2014 Medium

    Established PGRMC1/PGRMC2 as mitotic-spindle proteins that restrain cell-cycle entry, implicating it in division control via G3BP2.

    Evidence siRNA, pull-down, PLA, immunofluorescence, and FUCCI cell-cycle sensing

    PMID:25253729

    Open questions at the time
    • Molecular role at the spindle unclear
    • G3BP2 functional contribution undefined
  12. 2015 High

    Resolved PGRMC1's heme coordination chemistry (five-coordinate high-spin, axial Y95 tyrosinate) and demonstrated progesterone-induced spectral changes in heme-loaded protein.

    Evidence UV-vis/EPR spectroscopy, Y95 mutagenesis, and progesterone binding with purified protein

    PMID:25675345

    Open questions at the time
    • Physiological redox role of heme not established
    • Single-lab spectroscopic study
  13. 2015 Medium

    Showed Pgrmc1 is required for cell-surface EGFR and mPRα-dependent EGFR signaling in normal oocytes, generalizing its EGFR role beyond cancer.

    Evidence AG205 pharmacological inhibition, plasma-membrane fractionation, and oocyte maturation assays in zebrafish

    PMID:25720537

    Open questions at the time
    • Pharmacological inhibitor specificity
    • No genetic KO in this study
  14. 2016 High

    Provided the structural basis for PGRMC1 function: heme-stacking dimerization required for EGFR and P450 interactions, proliferation, and chemoresistance, with CO as a dimer disruptor.

    Evidence 1.95 Å crystal structure, CO interference, mutagenesis, co-IP, and cellular phenotype assays

    PMID:26988023

    Open questions at the time
    • Full-length/membrane context not crystallized
    • Dynamics of dimer-to-monomer switching in cells not quantified
  15. 2016 High

    Linked PGRMC1 to heme biosynthesis by showing it binds and modulates ferrochelatase and can donate heme to apo-cytochrome b5.

    Evidence Reciprocal AP-MS, in vitro FECH activity assay, and in vitro heme-transfer assay

    PMID:27599036

    Open questions at the time
    • In vivo significance of FECH modulation not established here
    • Directionality of heme flux in cells unresolved
  16. 2016 Medium

    Identified a direct interaction of PGRMC1 with Aurora Kinase B at the central spindle, tying it to karyokinesis and meiotic progression.

    Evidence siRNA, time-lapse imaging, AURKB co-localization, and AG205 inhibition in granulosa cells and oocytes

    PMID:27260975

    Open questions at the time
    • Direct biochemical AURKB binding not isolated
    • Role in spindle assembly mechanism undefined
  17. 2018 High

    Resolved the sigma-2 identity question, establishing TMEM97 as the primary sigma-2 receptor and defining a PGRMC1-TMEM97-LDLR ternary complex for LDL internalization.

    Evidence CRISPR KO with radioligand binding, PLA, and LDL uptake epistasis

    PMID:30443021

    Open questions at the time
    • Stoichiometry of the ternary complex undefined
    • Mechanism by which PGRMC1 promotes LDL uptake unclear
  18. 2018 Medium

    Provided in vivo genetic evidence that Pgrmc1 controls oocyte maturation through regulation of mPRα expression.

    Evidence CRISPR global KO in zebrafish with oocyte maturation assays and mPRα western blot

    PMID:30319543

    Open questions at the time
    • Mechanism linking PGRMC1 to mPRα stability not defined
    • Mammalian generalizability untested here
  19. 2018 Medium

    Reported a non-conventional plasma-membrane topology for cell-surface PGRMC1 with the C-terminal cytoplasmic domain exposed extracellularly.

    Evidence Flow cytometry, trypsin sensitivity, and GST-fusion epitope mapping with antibodies

    PMID:30679694

    Open questions at the time
    • How the topology arises mechanistically unknown
    • Functional consequence of surface exposure undefined
  20. 2018 Low

    Showed PGRMC1 colocalizes with and positions nucleolin in the nucleolus, though without a confirmed direct interaction.

    Evidence Immunofluorescence, siRNA, and PLA (negative for direct interaction) under oxidative stress

    PMID:29339453

    Open questions at the time
    • No direct PGRMC1-NCL interaction detected (negative PLA)
    • Mediating factor unidentified
    • Nucleolar function of PGRMC1 unclear
  21. 2020 Medium

    Demonstrated that PGRMC1 phosphorylation status broadly reprograms metabolism and tumor growth, with Y180 required for full tumorigenicity.

    Evidence Phospho-site mutagenesis (S57A/Y180F/S181A combinations), proteomics, metabolic assays, and xenografts in NSG mice

    PMID:32245408

    Open questions at the time
    • Kinases targeting these sites not identified
    • Direct mechanistic link from phospho-state to metabolism unresolved
  22. 2021 High

    Defined PGRMC1 as a size-selective ER-phagy cargo receptor for misfolded prohormones coupling to RTN3, revealing an organelle quality-control function.

    Evidence Reciprocal co-IP, RTN3 interactome proteomics, CRISPR/siRNA, and ER-phagy/trafficking assays in β-cells (two papers)

    PMID:34645803 PMID:34779709

    Open questions at the time
    • Structural basis of size selectivity unknown
    • Range of physiological cargoes incompletely defined
  23. 2021 High

    Showed PGRMC1 stabilizes a broad set of cytochromes P450 heme-independently and that Y113 axial coordination is required for ferrochelatase binding, dissociating stabilization from heme catalysis.

    Evidence Pgrmc1 KO mouse with proteomics, transcriptomics, in vitro P450 activity, and Y113F mutagenesis

    PMID:34678314

    Open questions at the time
    • How heme-independent stabilization occurs mechanistically unclear
    • Which P450s are physiologically most dependent unresolved
  24. 2021 Medium

    Linked PGRMC1 to progestin-driven proliferation via S181-dependent prohibitin binding that frees ERα for transcription.

    Evidence Co-IP/MS, S181A mutant analysis, ERα activity and proliferation assays with inhibitors

    PMID:34830790

    Open questions at the time
    • Direct PGRMC1-PHB binding interface unmapped
    • Generality beyond the cell models tested unknown
  25. 2021 Medium

    Showed PGRMC1 promotes ferroptosis in drug-tolerant persister cells via lipophagy and fatty-acid oxidation, identifying a context-dependent cell-death role.

    Evidence siRNA, overexpression, lipid-ROS measurement, autophagosome imaging, and xenografts

    PMID:34749765

    Open questions at the time
    • Molecular trigger linking PGRMC1 to lipophagy undefined
    • Reconciliation with its protective stress roles unresolved
  26. 2021 Medium

    Connected Pgrmc1 to hepatocarcinogenesis through an EGFR-NF-κB-IL-6 axis driving compensatory proliferation.

    Evidence Global Pgrmc1 KO in DEN-induced HCC, NF-κB/IL-6 assays, and erlotinib epistasis

    PMID:34069911

    Open questions at the time
    • Cell-type origin of the effect not isolated
    • Direct vs. indirect EGFR contribution incompletely separated
  27. 2022 Medium

    Identified PGRMC1 as a direct STIM1 coiled-coil binder that promotes store-operated Ca2+ entry and downstream NFAT and cytoskeletal signaling.

    Evidence Co-IP, PGRMC1 depletion, Ca2+ imaging, NFAT reporter, and focal-adhesion/actin imaging in breast cancer cells

    PMID:35045297

    Open questions at the time
    • Structural basis of STIM1 conformational promotion undefined
    • Relationship to ER heme/P450 functions unclear
  28. 2025 Medium

    Showed PGRMC1 binds PERK via ER luminal domains to activate PERK independent of ER stress, phosphorylating eIF2α and suppressing c-Myc translation to block HCC.

    Evidence Co-IP with domain mapping, PERK/eIF2α phosphorylation assays, and orthotopic HCC mouse model

    PMID:39747098

    Open questions at the time
    • How PGRMC1 binding activates PERK mechanistically undefined
    • Apparent contrast with tumor-promoting PGRMC1 roles unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how PGRMC1's distinct activities—heme chemistry, P450/EGFR stabilization, ER-phagy cargo receptor function, progesterone/mPRα signaling, SOCE, and PERK activation—are coordinated within a single protein and switched between tumor-suppressive and tumor-promoting outputs.
  • No unifying structural model of full-length membrane-embedded PGRMC1 in different complexes
  • Phospho-code-to-interaction mapping incomplete
  • Mechanism reconciling opposing roles in hepatocarcinogenesis unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 3 GO:0060090 molecular adaptor activity 2 GO:0008289 lipid binding 1 GO:0038024 cargo receptor activity 1
Localization
GO:0005886 plasma membrane 3 GO:0005783 endoplasmic reticulum 2 GO:0005815 microtubule organizing center 2 GO:0005634 nucleus 1
Pathway
R-HSA-1430728 Metabolism 3 R-HSA-162582 Signal Transduction 3 R-HSA-392499 Metabolism of proteins 3 R-HSA-1640170 Cell Cycle 2 R-HSA-9612973 Autophagy 2
Partners
AURKBEGFRFECHMPRΑPERKRTN3STIM1TMEM97
Complex memberships
PGRMC1-TMEM97-LDLR ternary complex

Evidence

Reading pass · 29 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2016 Crystal structure of the PGRMC1 cytosolic domain at 1.95 Å resolution reveals it forms a stable dimer through stacking interactions of two protruding heme molecules; the heme iron is five-coordinated by Tyr113. CO disrupts dimerization by binding to the sixth coordination site of heme. Haem-mediated dimerization is required for interactions with EGFR and cytochromes P450, cancer proliferation, and chemoresistance. X-ray crystallography, CO treatment, mutagenesis, co-immunoprecipitation, cell-based functional assays Nature Communications High 26988023
2008 PGRMC1 binds heme as its sole biochemical activity, shares homology with cytochrome b5-related proteins, and activates the P450 protein CYP51/lanosterol demethylase to regulate cholesterol synthesis. Binding partners include multiple P450 proteins, PAIR-BP1, and Insig. Biochemical binding assays, protein interaction studies (co-precipitation), enzymatic activity assays Pharmacology & Therapeutics Medium 18992768
2007 PGRMC1 directly binds progesterone at a single site (apparent Kd ~35 nM), requiring the entire molecule including transmembrane domain and initial C-terminus for maximal binding. PGRMC1 siRNA knockdown reduced [3H]P4 binding by 60% and abolished progesterone's antiapoptotic action in granulosa cells. PAIRBP1 binds PGRMC1 at C-terminal residues 70-130, distal to the putative P4 binding site. siRNA knockdown, [3H]progesterone binding assay with GFP-PGRMC1 fusion protein, deletion mutagenesis Endocrinology Medium 17991724
2015 Human PGRMC1 binds heme in a five-coordinate high-spin configuration with an axial tyrosinate ligand at Y95. Y95C or Y95F mutations dramatically reduce heme binding. Progesterone binds to heme-loaded hPGRMC1 and induces spectral changes indicating conformational changes to the heme, providing direct evidence for progesterone-binding activity. Spectroscopy (UV-vis, EPR), site-directed mutagenesis, redox potential measurement, progesterone binding assay with purified protein Biochemistry High 25675345
2010 PGRMC1 co-precipitates with EGFR, increases plasma membrane EGFR levels, co-localizes with EGFR in cytoplasmic vesicles, and co-fractionates with EGFR in high density microsomes. PGRMC1 increases susceptibility to EGFR inhibitors erlotinib and AG-1478. A PGRMC1 small molecule ligand destabilizes EGFR in tumor cell lines. Co-immunoprecipitation, subcellular fractionation, immunofluorescence co-localization, cell viability assays with EGFR inhibitors Journal of Biological Chemistry Medium 20538600
2011 A photoaffinity probe (WC-21) irreversibly labels sigma-2 receptors in rat liver membranes, and the labeled protein was identified as PGRMC1. Overexpression of PGRMC1 increases sigma-2 radioligand binding; knockdown decreases it. PGRMC1 and sigma-2 ligand SW120 co-localize with ER and mitochondrial markers in HeLa cells. Photoaffinity labeling, mass spectrometry identification, overexpression and siRNA knockdown with radioligand binding, immunocytochemistry Nature Communications Medium 21730960
2016 PGRMC1 interacts with ferrochelatase (FECH), the terminal enzyme of heme biosynthesis. This interaction was validated by reciprocal affinity purification/MS and confirmed in vitro and in HEK293T cells. In vitro, PGRMC1 decreases FECH activity in a dose-dependent manner, with strongest interaction for the FECH conformation associated with product release, suggesting PGRMC1 regulates heme release. PGRMC1 can donate heme to apo-cytochrome b5 in vitro. Affinity purification coupled with mass spectrometry, reciprocal co-IP/immunoblot, in vitro FECH activity assay, in vitro heme transfer assay Biochemistry High 27599036
2021 PGRMC1 binds and stabilizes a broad range of cytochromes P450 (>13 identified) in a heme-independent manner in mouse liver. Pgrmc1 knockout reduces cytochrome P450 protein levels post-transcriptionally and reduces P450 enzyme activity. The Y113F mutation (lacking axial heme iron coordination) retains heme binding but abolishes binding to ferrochelatase. Pgrmc1 knockout mouse model, proteomics, transcriptomics, in vitro P450 activity assays, mutagenesis Journal of Biological Chemistry High 34678314
2008 PGRMC1 is differentially phosphorylated between ER-positive and ER-negative breast tumors. Simultaneous mutation of serine-56 and serine-180 fully abrogates sensitivity of MCF7 cells to peroxide-induced cell death, indicating these phosphorylation sites regulate PGRMC1's role in oxidative stress response. 2D-PAGE proteomics, phosphatase treatment, site-directed mutagenesis of phosphorylation sites, oxidative stress survival assay in stable transfectants Breast Cancer Research Medium 18922159
2008 A missense mutation H165R in the cytochrome b5 domain of PGRMC1, associated with premature ovarian failure, abolishes binding of CYP7A1 to PGRMC1 and attenuates PGRMC1's ability to mediate the anti-apoptotic action of progesterone in ovarian cells. Mutation screening, protein binding assay (CYP7A1-PGRMC1 interaction), progesterone anti-apoptotic functional assay in ovarian cells Human Molecular Genetics Medium 18782852
2021 PGRMC1 acts as a size-selective cargo receptor for RTN3-dependent ER-phagy. Via its luminal domain, PGRMC1 binds misfolded prohormones (including mutant proinsulin and mutant POMC) and targets them for RTN3-dependent lysosomal degradation. PGRMC1 selectively recruits small oligomers rather than large aggregates. Chemical or genetic inactivation of PGRMC1 in pancreatic β-cells impairs mutant proinsulin turnover and restores WT proinsulin trafficking. Co-immunoprecipitation, proteomics (RTN3 interactome), siRNA knockdown, CRISPR knockout, confocal microscopy, cell-based ER-phagy assays Nature Communications High 34645803 34779709
2014 PGRMC1 acts as an adaptor protein that transports membrane progesterone receptor alpha (mPRα) to the cell surface. Stable overexpression of PGRMC1 increases cell-surface mPRα expression and specific [3H]progesterone binding characteristic of mPRα. PGRMC1 co-immunoprecipitates with mPRα. The antiapoptotic effects of progestins previously attributed to PGRMC1 were abolished by siRNA knockdown of mPRα, indicating they are mediated via mPRα. Stable transfection, [3H]progesterone binding assay, G-protein activation assay, co-immunoprecipitation, immunocytochemistry, siRNA knockdown of mPRα Endocrinology Medium 24424068
2018 PGRMC1, TMEM97, and LDL receptor form a ternary complex required for rapid internalization of LDL. CRISPR KO of PGRMC1 or TMEM97 individually reduced LDL uptake equally; double KO did not reduce it further. PGRMC1 KO reduced sigma-2 radioligand binding affinity but did not eliminate binding sites (TMEM97 KO eliminated [125I]RHM-4 binding), establishing TMEM97 as the primary sigma-2 receptor. CRISPR/Cas9 knockout, radioligand binding assays, confocal microscopy, proximity ligation assay, fluorescent/radiolabeled LDL internalization assay Scientific Reports High 30443021
2014 PGRMC1 and PGRMC2 interact with each other (demonstrated by pull-down assays, co-localization, and proximity ligation assays) and both localize to the mitotic spindle. Depletion of either protein increases entry into the cell cycle and causes metaphase arrest and apoptosis. Both PGRMC1 and PGRMC2 bind GTPase-activating protein-binding protein 2 (G3BP2), and G3BP2 siRNA similarly promotes cell cycle entry. siRNA knockdown, pull-down assay, proximity ligation assay, immunofluorescence co-localization, FUCCI cell cycle sensor Biology of Reproduction Medium 25253729
2012 Progesterone (P4) induces SUMOylation of PGRMC1 (interaction with SUMO-1 detected by co-immunoprecipitation and proximity ligation assay); SUMOylated PGRMC1 localizes to the nucleus. PGRMC1 mediates P4 suppression of Tcf/Lef transcriptional activity, and mutation of all PGRMC1 SUMOylation sites abolishes P4's ability to suppress Tcf/Lef activity. Co-immunoprecipitation with SUMO-1, proximity ligation assay, nuclear fractionation, Tcf/Lef reporter assay, PGRMC1 sumoylation site mutagenesis Endocrinology Medium 22719051
2012 Progesterone-induced BDNF release from glia requires Pgrmc1. siRNA knockdown of Pgrmc1 in C6 glial cells and primary astrocytes abolished P4-induced BDNF release. P4-induced BDNF release was mediated by ERK5 (not ERK1/2), placing Pgrmc1 upstream of ERK5 in this signaling cascade. siRNA knockdown, BDNF ELISA/measurement, pharmacological inhibition of PR vs. Pgrmc1-dependent signaling, ERK5 inhibition Endocrinology Medium 22778217
2016 PGRMC1 participates in late mitotic and meiotic events by directly interacting with Aurora Kinase B (AURKB) at the central spindle of dividing cells. PGRMC1 siRNA silencing in bovine granulosa cells caused G2/M arrest and defects in karyokinesis. PGRMC1 inhibition or silencing in oocytes impaired first polar body extrusion and caused meiotic figure aberrations. siRNA knockdown, time-lapse imaging, co-localization of PGRMC1 with AURKB, pharmacological inhibition with AG205, flow cytometry cell cycle analysis Cell Cycle Medium 27260975
2015 PGRMC1 co-localizes with mPRα and mPRα-dependent EGFR signaling in zebrafish oocytes. Pharmacological inhibition of PGRMC1 with AG205 blocks estradiol/GPER-mediated inhibition of oocyte maturation and decreases EGFR expression on oocyte plasma membranes, indicating Pgrmc1 is required for cell-surface EGFR expression and function in normal cells. Pharmacological inhibition (AG205), western blot of plasma membrane fractions, oocyte maturation functional assay, EGFR inhibitor co-treatment Journal of Endocrinology Medium 25720537
2003 HPR6.6/PGRMC1 expression in MCF-7 breast cancer cells sensitizes them to oxidative damage-induced cell death (H2O2 treatment). Cell death was not through typical apoptosis and corresponded with hyperphosphorylation of Akt and IκB, but inhibition of Akt or IκB degradation had no effect on HPR6.6-mediated death, indicating a novel oxidative damage response pathway. Overexpression of HPR6.6/PGRMC1, H2O2 treatment, pharmacological inhibition of Akt/IκB, cell death assays Journal of Cellular Biochemistry Low 14523988
2019 Cell surface-expressed PGRMC1 (csPGRMC1) displays a non-conventional plasma membrane topology in which the C-terminal cytoplasmic domain (residues 171-195) is exposed extracellularly, as determined by epitope mapping of anti-PGRMC1 monoclonal antibodies and trypsin sensitivity assays. Flow cytometry, trypsin treatment, GST-fused PGRMC1 deletion/mutant epitope mapping, polyclonal antibody binding assays Scientific Reports Medium 30679694
2022 PGRMC1 promotes store-operated Ca2+ entry (SOCE) by directly binding to the coiled-coil domain of STIM1 and promoting STIM1 conformational switch. PGRMC1 depletion decreased SOCE, impaired NFAT pathway activation, and disrupted EGF-induced focal adhesion turnover and actomyosin formation in breast cancer cells. Complementation-dependent in situ labeling (co-IP discovery), genetic depletion (PGRMC1 KD), Ca2+ imaging, NFAT reporter assay, focal adhesion and actin cytoskeleton imaging Cell Reports Medium 35045297
2021 PGRMC1 promotes ferroptosis in paclitaxel-tolerant persister cancer cells by increasing fatty acid oxidation and lipophagy via autophagosome formation. PGRMC1 silencing reduced ferroptosis sensitivity to xCT inhibitors; PGRMC1 overexpression in parental cells enhanced ferroptosis. PGRMC1 co-localized with LC3B-II. siRNA silencing, PGRMC1 overexpression, lipid ROS measurement, autophagosome imaging, mouse xenograft experiments Journal of Experimental & Clinical Cancer Research Medium 34749765
2025 PGRMC1, localized to the ER membrane, interacts with PERK through their ER luminal domains. This interaction activates PERK in an ER stress-independent manner, leading to eIF2α phosphorylation and consequent inhibition of c-Myc protein translation, blocking hepatocellular carcinoma formation. Co-immunoprecipitation (ER luminal domain interaction), PERK phosphorylation assays, eIF2α phosphorylation assays, orthotopic HCC mouse model, ER localization confirmed by subcellular fractionation/imaging Nature Communications Medium 39747098
2021 PGRMC1 promotes progestin-dependent breast cancer cell proliferation by binding prohibitin-1 (PHB1) and prohibitin-2 (PHB2) in a manner dependent on S181 phosphorylation. PGRMC1-PHB interaction competitively displaces PHBs from ERα, allowing ERα transcriptional activation. Inhibition of PGRMC1 or ERα abolished this proliferative effect. Co-immunoprecipitation with mass spectrometry, phosphorylation mutant (S181A) analysis, ERα activity assays, cell proliferation assays, inhibitor experiments Cancers Medium 34830790
2018 Pgrmc1 knockout in zebrafish reduces mPRα protein expression and reduces oocyte sensitivity to progestin, resulting in impaired meiotic maturation and reduced fertility. This provides in vivo evidence that Pgrmc1 regulates oocyte maturation via regulation of mPRα expression. CRISPR/Cas9 global knockout in zebrafish, in vivo and in vitro oocyte maturation assays, western blot for mPRα levels Frontiers in Endocrinology Medium 30319543
2020 Manipulation of PGRMC1 phosphorylation status (S57A/S181A double mutant or S57A/Y180F/S181A triple mutant) in cancer cells broadly alters energy metabolism, glycolysis, PI3K/AKT activity, cell shape, actin cytoskeleton, mitochondrial properties, and tumor growth. Y180F mutation strongly attenuates xenograft tumor growth, indicating Y180 phosphorylation is required for full tumorigenic activity. PGRMC1 phosphorylation site mutagenesis, proteomics, metabolic assays, PI3K/AKT phosphorylation assays, xenograft tumor growth in NOD-SCID gamma mice BMC Molecular and Cell Biology Medium 32245408
2013 P4 antagonism of E2-induced neurite outgrowth requires microglial expression of Pgrmc1/S2R. siRNA knockdown of Pgrmc1 in microglia suppressed P4-E2 antagonism of neurite outgrowth. Conditioned media from activated (LPS or wound-stimulated) microglia restored P4-E2 antagonism, but only if Pgrmc1 was present, indicating Pgrmc1 mediates microglial activation and the release of soluble factors that antagonize neurite growth. siRNA knockdown, co-culture system (neurons/astrocytes/microglia), conditioned media transfer, LPS/wound activation, neurite outgrowth quantification Endocrinology Medium 23653459
2018 PGRMC1 colocalizes with nucleolin (NCL) in the nucleolus of bovine granulosa cells and oocytes. PGRMC1 siRNA depletion causes NCL translocation from the nucleolus to the nucleoplasm; oxidative stress also reduces nucleolar PGRMC1 and redistributes NCL. However, direct PGRMC1-NCL interaction was not detected by proximity ligation assay, suggesting additional mediators. Immunofluorescence, siRNA knockdown, proximity ligation assay (negative for direct interaction), H2O2 oxidative stress treatment Reproduction Low 29339453
2021 PGRMC1 loss in a diethylnitrosamine-induced murine HCC model suppresses hepatocarcinogenesis by reducing NF-κB-dependent IL-6 production, which reduces compensatory hepatocyte proliferation. The anti-pro-inflammatory effect is mediated through reduced EGFR levels, as EGFR inhibitor erlotinib abolished the additional effect of PGRMC1 loss. Global Pgrmc1 knockout mouse, DEN-induced HCC model, NF-κB activity assay, IL-6 ELISA, EGFR protein measurement, pharmacological EGFR inhibition epistasis Cancers Medium 34069911

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 Identification of the PGRMC1 protein complex as the putative sigma-2 receptor binding site. Nature communications 272 21730960
2008 PGRMC1 (progesterone receptor membrane component 1): a targetable protein with multiple functions in steroid signaling, P450 activation and drug binding. Pharmacology & therapeutics 172 18992768
2014 Alzheimer's therapeutics targeting amyloid beta 1-42 oligomers II: Sigma-2/PGRMC1 receptors mediate Abeta 42 oligomer binding and synaptotoxicity. PloS one 171 25390692
2007 Progesterone receptor membrane component-1 (PGRMC1) is the mediator of progesterone's antiapoptotic action in spontaneously immortalized granulosa cells as revealed by PGRMC1 small interfering ribonucleic acid treatment and functional analysis of PGRMC1 mutations. Endocrinology 156 17991724
2016 Haem-dependent dimerization of PGRMC1/Sigma-2 receptor facilitates cancer proliferation and chemoresistance. Nature communications 154 26988023
2010 Progesterone receptor membrane component 1 (Pgrmc1): a heme-1 domain protein that promotes tumorigenesis and is inhibited by a small molecule. The Journal of pharmacology and experimental therapeutics 120 20164297
2014 Enhancement of cell surface expression and receptor functions of membrane progestin receptor α (mPRα) by progesterone receptor membrane component 1 (PGRMC1): evidence for a role of PGRMC1 as an adaptor protein for steroid receptors. Endocrinology 116 24424068
2010 Pgrmc1 (progesterone receptor membrane component 1) associates with epidermal growth factor receptor and regulates erlotinib sensitivity. The Journal of biological chemistry 114 20538600
2018 Sigma-2 Receptor/TMEM97 and PGRMC-1 Increase the Rate of Internalization of LDL by LDL Receptor through the Formation of a Ternary Complex. Scientific reports 112 30443021
2008 Breast cancer proteomics reveals correlation between estrogen receptor status and differential phosphorylation of PGRMC1. Breast cancer research : BCR 99 18922159
2008 Alterations in the expression, structure and function of progesterone receptor membrane component-1 (PGRMC1) in premature ovarian failure. Human molecular genetics 97 18782852
2021 PGRMC1-dependent lipophagy promotes ferroptosis in paclitaxel-tolerant persister cancer cells. Journal of experimental & clinical cancer research : CR 94 34749765
2016 A Novel Role for Progesterone Receptor Membrane Component 1 (PGRMC1): A Partner and Regulator of Ferrochelatase. Biochemistry 93 27599036
2016 The emerging role of progesterone receptor membrane component 1 (PGRMC1) in cancer biology. Biochimica et biophysica acta 87 27452206
2017 ANP promotes proliferation and inhibits apoptosis of ovarian granulosa cells by NPRA/PGRMC1/EGFR complex and improves ovary functions of PCOS rats. Cell death & disease 81 29072679
2012 Progesterone increases the release of brain-derived neurotrophic factor from glia via progesterone receptor membrane component 1 (Pgrmc1)-dependent ERK5 signaling. Endocrinology 80 22778217
2020 The Sigma-2 Receptor/TMEM97, PGRMC1, and LDL Receptor Complex Are Responsible for the Cellular Uptake of Aβ42 and Its Protein Aggregates. Molecular neurobiology 70 32572762
2012 Endometrial miR-181a and miR-98 expression is altered during transition from normal into cancerous state and target PGR, PGRMC1, CYP19A1, DDX3X, and TIMP3. The Journal of clinical endocrinology and metabolism 65 22492871
2012 S2R(Pgrmc1): the cytochrome-related sigma-2 receptor that regulates lipid and drug metabolism and hormone signaling. Expert opinion on drug metabolism & toxicology 62 22292588
2003 Hpr6.6 protein mediates cell death from oxidative damage in MCF-7 human breast cancer cells. Journal of cellular biochemistry 61 14523988
2015 Elements in support of the 'non-identity' of the PGRMC1 protein with the σ2 receptor. European journal of pharmacology 56 25843410
2014 Progesterone receptor membrane component-1 (PGRMC1) and PGRMC-2 interact to suppress entry into the cell cycle in spontaneously immortalized rat granulosa cells. Biology of reproduction 55 25253729
2015 Spectroscopic and mutagenesis studies of human PGRMC1. Biochemistry 54 25675345
2017 PGRMC1-dependent autophagy by hyperoside induces apoptosis and sensitizes ovarian cancer cells to cisplatin treatment. International journal of oncology 51 28197632
2013 PGRMC1 and PGRMC2 in uterine physiology and disease. Frontiers in neuroscience 49 24065879
2017 Thoughts on interactions between PGRMC1 and diverse attested and potential hydrophobic ligands. The Journal of steroid biochemistry and molecular biology 48 28104494
2015 Role of Pgrmc1 in estrogen maintenance of meiotic arrest in zebrafish oocytes through Gper/Egfr. The Journal of endocrinology 47 25720537
2010 Down-regulation of progesterone receptor membrane component 1 (PGRMC1) in peripheral nucleated blood cells associated with premature ovarian failure (POF) and polycystic ovary syndrome (PCOS). Reproductive biology and endocrinology : RB&E 46 20537145
2021 PGRMC1 acts as a size-selective cargo receptor to drive ER-phagic clearance of mutant prohormones. Nature communications 45 34645803
2019 TMEM97 and PGRMC1 do not mediate sigma-2 ligand-induced cell death. Cell death discovery 44 30701090
2011 Differential responses of progesterone receptor membrane component-1 (Pgrmc1) and the classical progesterone receptor (Pgr) to 17β-estradiol and progesterone in hippocampal subregions that support synaptic remodeling and neurogenesis. Endocrinology 43 22147012
2010 Changes in PGRMC1, a potential progesterone receptor, in human myometrium during pregnancy and labour at term and preterm. Molecular human reproduction 43 21131300
2015 Progestin and AdipoQ Receptor 7, Progesterone Membrane Receptor Component 1 (PGRMC1), and PGRMC2 and Their Role in Regulating Progesterone's Ability to Suppress Human Granulosa/Luteal Cells from Entering into the Cell Cycle. Biology of reproduction 42 26203174
2022 Ultrasound-triggered microbubble destruction enhances the radiosensitivity of glioblastoma by inhibiting PGRMC1-mediated autophagy in vitro and in vivo. Military Medical Research 41 35152910
2013 Possible role of PGRMC1 in breast cancer development. Climacteric : the journal of the International Menopause Society 41 23758160
2012 Progesterone regulation of progesterone receptor membrane component 1 (PGRMC1) sumoylation and transcriptional activity in spontaneously immortalized granulosa cells. Endocrinology 41 22719051
2013 Progesterone antagonism of neurite outgrowth depends on microglial activation via Pgrmc1/S2R. Endocrinology 39 23653459
2018 Pgrmc1 Knockout Impairs Oocyte Maturation in Zebrafish. Frontiers in endocrinology 38 30319543
2016 Sigma-2 receptor and progesterone receptor membrane component 1 (PGRMC1) are two different proteins: Proofs by fluorescent labeling and binding of sigma-2 receptor ligands to PGRMC1. Pharmacological research 37 28007569
2014 Progesterone receptor membrane component 1 (PGRMC1) expression in fetal membranes among women with preterm premature rupture of the membranes (PPROM). Placenta 37 24680695
2021 Progesterone receptor membrane component 1 (PGRMC1) binds and stabilizes cytochromes P450 through a heme-independent mechanism. The Journal of biological chemistry 34 34678314
2020 PGRMC1 phosphorylation affects cell shape, motility, glycolysis, mitochondrial form and function, and tumor growth. BMC molecular and cell biology 34 32245408
2016 PGRMC1 regulation by phosphorylation: potential new insights in controlling biological activity. Oncotarget 34 27448967
2015 PGRMC1 contributes to doxorubicin-induced chemoresistance in MES-SA uterine sarcoma. Cellular and molecular life sciences : CMLS 32 25596698
2016 PGRMC1 Elevation in Multiple Cancers and Essential Role in Stem Cell Survival. Advances in lung cancer (Irvine) 30 27867772
2016 PGRMC1 participates in late events of bovine granulosa cells mitosis and oocyte meiosis. Cell cycle (Georgetown, Tex.) 29 27260975
2008 PGRMC1: a new biomarker for the estrogen receptor in breast cancer. Breast cancer research : BCR 29 19090968
2016 Pgrmc1/BDNF Signaling Plays a Critical Role in Mediating Glia-Neuron Cross Talk. Endocrinology 27 26990062
2019 Downregulation of nuclear progestin receptor (Pgr) and subfertility in double knockouts of progestin receptor membrane component 1 (pgrmc1) and pgrmc2 in zebrafish. General and comparative endocrinology 26 31536721
2017 The evolutionary appearance of signaling motifs in PGRMC1. Bioscience trends 26 28250339
2021 Progesterone Receptor Membrane Component (PGRMC)1 and PGRMC2 and Their Roles in Ovarian and Endometrial Cancer. Cancers 25 34885064
2022 PGRMC1: An enigmatic heme-binding protein. Pharmacology & therapeutics 24 36463977
2021 PGRMC Proteins Are Coming of Age: A Special Issue on the Role of PGRMC1 and PGRMC2 in Metabolism and Cancer Biology. Cancers 24 33572771
2010 Transcriptional analysis of novel hormone receptors PGRMC1 and PGRMC2 as potential biomarkers of breast adenocarcinoma staging. The Journal of surgical research 24 20655063
2020 Identification of PGRMC1 as a Candidate Oncogene for Head and Neck Cancers and Its Involvement in Metabolic Activities. Frontiers in bioengineering and biotechnology 23 31970154
2018 PGRMC1/2 promotes luteal vascularization and maintains the primordial follicles of mice. Reproduction (Cambridge, England) 23 30306772
2017 Dynamic expression of PGRMC1 and SERBP1 in human endometrium: an implication in the human decidualization process. Fertility and sterility 23 28911927
2013 Pgrmc1: new roles in the microglial mediation of progesterone-antagonism of estradiol-dependent neurite sprouting and in microglial activation. Frontiers in neuroscience 23 24027494
2020 Protein complexes including PGRMC1 and actin-associated proteins are disrupted by AG-205. Biochemical and biophysical research communications 22 31980178
2018 Progesterone maintains the status of granulosa cells and slows follicle development partly through PGRMC1. Journal of cellular physiology 22 30069867
2016 Norbenzomorphan Framework as a Novel Scaffold for Generating Sigma 2 Receptor/PGRMC1 Subtype-Selective Ligands. ChemMedChem 22 26915462
2022 PGRMC1 Regulates Cellular Senescence via Modulating FOXO1 Expression in Decidualizing Endometrial Stromal Cells. Biomolecules 21 36008941
2021 PGRMC1 Promotes Progestin-Dependent Proliferation of Breast Cancer Cells by Binding Prohibitins Resulting in Activation of ERα Signaling. Cancers 21 34830790
2017 PGRMC1 Is a Novel Potential Tumor Biomarker of Human Renal Cell Carcinoma Based on Quantitative Proteomic and Integrative Biological Assessments. PloS one 21 28107520
2016 The PGRMC1 Protein Level Correlates with the Binding Activity of a Sigma-2 Fluorescent Probe (SW120) in Rat Brain Cells. Molecular imaging and biology 21 26335282
2016 Cystathionine β-synthase and PGRMC1 as CO sensors. Free radical biology & medicine 21 27565814
2013 Lipid synthesis and processing proteins ABHD5, PGRMC1 and squalene synthase can serve as novel immunohistochemical markers for sebaceous neoplasms and differentiate sebaceous carcinoma from sebaceoma and basal cell carcinoma with clear cell features. Journal of cutaneous pathology 21 23557589
2020 Novel nonclassic progesterone receptor PGRMC1 pulldown-precipitated proteins reveal a key role during human decidualization. Fertility and sterility 20 32386616
2015 May progesterone receptor membrane component 1 (PGRMC1) predict the risk of breast cancer? Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology 20 26303031
2019 Progestogens and PGRMC1-dependent breast cancer tumor growth: An in-vitro and xenograft study. Maturitas 19 31027671
2020 PGRMC1 effects on metabolism, genomic mutation and CpG methylation imply crucial roles in animal biology and disease. BMC molecular and cell biology 18 32293262
2018 PGRMC1 localization and putative function in the nucleolus of bovine granulosa cells and oocytes. Reproduction (Cambridge, England) 17 29339453
2018 Function and structural regulation of the carbon monoxide (CO)-responsive membrane protein PGRMC1. Journal of clinical biochemistry and nutrition 17 30087538
2023 PGRMC1 promotes triple-negative breast cancer cell growth via suppressing ferroptosis. Climacteric : the journal of the International Menopause Society 16 36724820
2021 Loss of PGRMC1 Delays the Progression of Hepatocellular Carcinoma via Suppression of Pro-Inflammatory Immune Responses. Cancers 16 34069911
2020 PGRMC1 Inhibits Progesterone-Evoked Proliferation and Ca2+ Entry Via STIM2 in MDA-MB-231 Cells. International journal of molecular sciences 16 33076541
2019 Role of PGRMC1 in cell physiology of cervical cancer. Life sciences 16 31216441
2019 Increase in FoxP3, CD56 immune cells and decrease in glands PGRMC1 expression in the endometrium are associated with recurrent miscarriages. European journal of obstetrics, gynecology, and reproductive biology 15 31891895
2015 Hyaluronic acid prevents immunosuppressive drug-induced ovarian damage via up-regulating PGRMC1 expression. Scientific reports 15 25558795
2021 AG-205 Upregulates Enzymes Involved in Cholesterol Biosynthesis and Steroidogenesis in Human Endometrial Cells Independently of PGRMC1 and Related MAPR Proteins. Biomolecules 14 34680104
2022 Metastasis enhancer PGRMC1 boosts store-operated Ca2+ entry by uncoiling Ca2+ sensor STIM1 for focal adhesion turnover and actomyosin formation. Cell reports 13 35045297
2016 Expression of Progesterone Receptor Membrane Component 1 (PGRMC1), Progestin and AdipoQ Receptor 7 (PAQPR7), and Plasminogen Activator Inhibitor 1 RNA-Binding Protein (PAIRBP1) in Glioma Spheroids In Vitro. BioMed research international 13 27340667
2023 Progesterone Receptor Membrane Component 1 (PGRMC1) Modulates Tumour Progression, the Immune Microenvironment and the Response to Therapy in Glioblastoma. Cells 12 37887342
2021 Deciphering the Role of PGRMC1 During Human Decidualization Using an In Vitro Approach. The Journal of clinical endocrinology and metabolism 12 33955452
2021 Clozapine Induced Disturbances in Hepatic Glucose Metabolism: The Potential Role of PGRMC1 Signaling. Frontiers in endocrinology 12 34970218
2025 Liver-specific gene PGRMC1 blocks c-Myc-induced hepatocarcinogenesis through ER stress-independent PERK activation. Nature communications 11 39747098
2020 Association of circulating Progesterone Receptor Membrane Component-1 (PGRMC1) with PGRMC1 expression in breast tumour tissue and with clinical breast tumour characteristics. Maturitas 11 32972637
2023 New Insights on the Progesterone (P4) and PGRMC1/NENF Complex Interactions in Colorectal Cancer Progression. Cancers 10 37894441
2020 PGRMC1 in animal breast cancer tissue and blood is associated with increased tumor growth with norethisterone in contrast to progesterone and dydrogesterone: four-arm randomized placebo-controlled xenograft study. Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology 10 32208774
2019 Epitope mapping of anti-PGRMC1 antibodies reveals the non-conventional membrane topology of PGRMC1 on the cell surface. Scientific reports 10 30679694
2023 PGRMC1 Ablation Protects from Energy-Starved Heart Failure by Promoting Fatty Acid/Pyruvate Oxidation. Cells 9 36899888
2023 Olanzapine-induced nonalcoholic fatty liver disease: The effects of differential food pattern and the involvement of PGRMC1 signaling. Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association 9 37019375
2021 MicroRNA-181a suppresses norethisterone-promoted tumorigenesis of breast epithelial MCF10A cells through the PGRMC1/EGFR-PI3K/Akt/mTOR signaling pathway. Translational oncology 9 33730679
2019 PGRMC1 can trigger estrogen-dependent proliferation of breast cancer cells: estradiol vs. equilin vs. ethinylestradiol. Climacteric : the journal of the International Menopause Society 9 30862292
2023 Insight into mitochondrial dysfunction mediated by clozapine-induced inhibition of PGRMC1 in PC12 cells. Toxicology 8 37087062
2022 E2 + norethisterone promotes the PI3K-AKT pathway via PGRMC1 to induce breast cancer cell proliferation. Climacteric : the journal of the International Menopause Society 8 35137666
2021 A 127 kb truncating deletion of PGRMC1 is a novel cause of X-linked isolated paediatric cataract. European journal of human genetics : EJHG 8 33867527
2021 The ER transmembrane protein PGRMC1 recruits misfolded proteins for reticulophagic clearance. Autophagy 8 34779709
2018 Triple A patient cells suffering from mitotic defects fail to localize PGRMC1 to mitotic kinetochore fibers. Cell division 8 30455725
2015 Progesterone Receptor Membrane Component 1 (PGRMC1) Expression in Murine Retina. Current eye research 7 26642738

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