The development of simultaneous resistance to multiple structurally unrelated drugs is a major impediment to cancer chemotherapy. Shen et al. (1986) showed that multidrug resistance in human KB carcinoma cells selected in colchicine, vinblastine, or adriamycin is associated with amplification of specific DNA sequences termed the multidrug resistance
locus (MDR1). Increased expression and amplification of MDR1 sequences were also found in multidrug-resistant sublines of human leukemia and ovarian carcinoma cells. Overexpression of P-glycoprotein-1 appears to be a consistent feature of mammalian cells displaying resistance to multiple anticancer drugs and has been postulated to
mediate resistance.
NCBI Summary:
The membrane-associated protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intra-cellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the MDR/TAP subfamily. Members of the MDR/TAP subfamily are involved in multidrug resistance. The protein encoded by this gene is an ATP-dependent drug efflux pump for xenobiotic compounds with broad substrate specificity. It is responsible for decreased drug accumulation in multidrug-resistant cells and often mediates the development of resistance to anticancer drugs. This protein also functions as a transporter in the blood-brain barrier. Mutations in this gene are associated with colchicine resistance and Inflammatory bowel disease 13. Alternative splicing and the use of alternative promoters results in multiple transcript variants. [provided by RefSeq, Feb 2017]
General function
Channel/transport protein
Comment
MDR1 is an ATP-dependent transmembrane pump protein localized to the plasma membrane.
Cellular localization
Plasma membrane
Comment
Ovarian function
Steroid metabolism
Comment
Edelman et al. (1999) propose that Cmdr1 in ovarian cells could be involved in the cell type-specific transport or release of estrogen that is essential for avian follicular development.
Expression regulated by
Steroids
Comment
Progesterone regulation of the expression and function of multidrug resistance type I in porcine granulosa cells.
Reprod Toxicol. 2005 .
Progesterone-dependent and -independent expression of the multidrug resistance type I gene in porcine granulosa cells. Fukuda H et al. A primary role of plasma membrane P-glycoprotein (P-gp), encoded by multidrug resistance type I (MDR1), is to protect against naturally occurring xenotoxics. Progesterone (P(4)) profoundly influences MDR1 expression in granulosa cells and luteal cells. Here, P(4) regulation of MDR1 expression was investigated in porcine granulosa cells using the P(4)-mediated promoter activity assay and a P4 receptor (PR) antagonist (RU-486). The promoter activity was measured chronologically for 48 h in cells transfected with the PR response element-containing pGL3. LH could stimulate the promoter activity through endogenous P4, with a maximum activity at 5 h. MDR1 mRNA level was highly maintained at 24-36 h. Conversely, exogenous P4 prolonged the promoter activity to further 10 h, and the high level of MDR1 mRNA was maintained even at 48 h. RU-486 completely inhibited the promoter activity, but the level of MDR1 mRNA rapidly increased in the presence of RU-486. The granulosa cells may become susceptible to RU-486 as a xenotoxic to rapidly express MDR1 for protection against it. These results indicate that MDR1 is expressed in porcine granulosa cells through P4-dependent and -independent regulations.
Ovarian localization
Oocyte, Granulosa, Theca, Luteal cells
Comment
RUNX2 Transcription Factor Regulates Gene Expression in Luteinizing Granulosa Cells of Rat Ovaries. Park ES et al. The LH surge promotes terminal differentiation of follicular cells to become luteal cells. RUNX2 has been shown to play an important role in cell differentiation, but the regulation of Runx2 expression and its function in the ovary remain to be determined. The present study examined 1) the expression profile of Runx2 and its partner CBFbeta during the periovulatory period, 2) regulatory mechanisms of Runx2 expression, and 3) its potential function in the ovary. Runx2 expression was induced in periovulatory granulosa cells of human and rodent ovaries. RUNX2 and core binding factor-beta (CBFbeta) proteins in nuclear extracts and RUNX2 binding to a consensus binding sequence increased after human chorionic gonadotropin (hCG) administration. This in vivo up-regulation of Runx2 expression was recapitulated in vitro in preovulatory granulosa cells by stimulation with hCG. The hCG-induced Runx2 expression was reduced by antiprogestin (RU486) and EGF-receptor tyrosine kinase inhibitor (AG1478), indicating the involvement of EGF-signaling and progesterone-mediated pathways. We also found that in the C/EBPbeta knockout mouse ovary, Runx2 expression was reduced, indicating C/EBPbeta-mediated expression. Next, the function of RUNX2 was investigated by suppressing Runx2 expression by small interfering RNA in vitro. Runx2 knockdown resulted in reduced levels of mRNA for Rgc32, Ptgds, Fabp6, Mmp13, and Abcb1a genes. Chromatin immunoprecipitation analysis demonstrated the binding of RUNX2 in the promoter region of these genes, suggesting that these genes are direct downstream targets of RUNX2. Collectively, the present data indicate that the LH surge-induced RUNX2 is involved in various aspects of luteal function by directly regulating the expression of diverse luteal genes.
Lee et al. (1998) localized MDR1 on the plasma membrane of granulosa cells but not of oocytes or thecal/interstitial cells, in normal prepubertal rats. It is also found in granulosa cells of preovulatory follicles and in cells of the corpora lutea. In contrast, Edelmann et al. (1999) showed that chicken mdr1 is expressed in ovarian tissues, particularly in theca cells, the major site for ovarian estrogen production in birds. Takebayashi Y, et al 2001 reported the expression of multidrug resistance associated transporters
(MDR1, MRP1, LRP and BCRP) in porcine oocyte.
Transporters such as P-glycoprotein (MDR1), multidrug resistance protein 1 (MRP1), lung resistance-related protein (LRP) and breast cancer resistance protein (BCRP) are associated with multidrug resistance in various carcinoma
cell lines. The expression of these molecules has been also characterized in human normal tissues. Their expression in porcine oocyte were examined by
reverse transcriptase-polymerase chain reaction. MDR1, MRP1 and LRP genes, but not BCRP gene were found to be expressed in porcine oocyte.
Follicle stages
Antral, Preovulatory, Corpus luteum
Comment
Phenotypes
Mutations
2 mutations
Species: mouse
Mutation name: None
type: null mutation fertility: fertile Comment:Schinkel et al. (1994) generated mice homozygous for a disruption of the mdr1a gene. The mice were viable and fertile and appeared phenotypically normal, but they displayed an increased sensitivity to the centrally neurotoxic pesticide ivermectin (100-fold) and to the carcinostatic drug vinblastine (3-fold).
Species: mouse
Mutation name: type: null mutation fertility: fertile Comment: Dysfunctional MDR-1 disrupts mitochondrial homeostasis in the oocyte and ovary. Clark H et al. (2019) Multidrug resistance transporters (MDRs) are best known for their pathological role in neoplastic evasion of chemotherapeutics and antibiotics. Here we show that MDR-1 is present in the oocyte mitochondrial membrane, and it protects the female gamete from oxidative stress. Female mdr1a mutant mice have no significant difference in ovarian follicular counts and stages, nor in reproductively functioning hormone levels, yet these mice are significantly more vulnerable to gonadotoxic chemotherapy, have chronically elevated reactive oxygen species in immature germinal vesicle oocytes, exhibit a significant over-accumulation of metabolites involved in the tricarboxylic acid cycle (TCA), and have abnormal mitochondrial membrane potential. The mdr1a mutant ovaries have a dramatically different transcriptomic profile with upregulation of genes involved in metabolism. Our findings indicate that functionality of MDR-1 reveals a critical intersection of metabolite regulation, oxidative stress, and mitochondrial dysfunction that has direct implications for human infertility, premature reproductive aging due to oxidative stress, and gonadoprotection.//////////////////