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. 1992 Dec;11(12):4291–4303. doi: 10.1002/j.1460-2075.1992.tb05528.x

The multidrug resistance and cystic fibrosis genes have complementary patterns of epithelial expression.

A E Trezise 1, P R Romano 1, D R Gill 1, S C Hyde 1, F V Sepúlveda 1, M Buchwald 1, C F Higgins 1
PMCID: PMC557002  PMID: 1385112

Abstract

The cystic fibrosis gene product, CFTR, and the multidrug resistance P-glycoprotein (encoded by the MDR1 gene) are structurally related proteins and both are associated with epithelial chloride channel activities. We have compared their cell-specific expression in the rat by in situ hybridization. In all tissues examined the two genes were found to have complementary patterns of expression, demonstrating exquisite regulation in both cell-specific and temporal fashions. Additionally, a switch in expression from one gene to the other was observed in certain tissues. For example, expression in the intestine switches from CFTR to MDR1 as the cells migrate across the crypt-villus boundary. A switch from CFTR to MDR1 expression was also observed in the uterine epithelium upon pregnancy. These data suggest that CFTR and P-glycoprotein serve analogous roles in epithelial cells and provide additional evidence that P-glycoprotein has a physiological role in regulating epithelial cell volume. The patterns of expression suggest that the regulation of these two genes is coordinately controlled.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Anderson M. P., Gregory R. J., Thompson S., Souza D. W., Paul S., Mulligan R. C., Smith A. E., Welsh M. J. Demonstration that CFTR is a chloride channel by alteration of its anion selectivity. Science. 1991 Jul 12;253(5016):202–205. doi: 10.1126/science.1712984. [DOI] [PubMed] [Google Scholar]
  2. Arceci R. J., Baas F., Raponi R., Horwitz S. B., Housman D., Croop J. M. Multidrug resistance gene expression is controlled by steroid hormones in the secretory epithelium of the uterus. Mol Reprod Dev. 1990 Feb;25(2):101–109. doi: 10.1002/mrd.1080250202. [DOI] [PubMed] [Google Scholar]
  3. Arceci R. J., Croop J. M., Horwitz S. B., Housman D. The gene encoding multidrug resistance is induced and expressed at high levels during pregnancy in the secretory epithelium of the uterus. Proc Natl Acad Sci U S A. 1988 Jun;85(12):4350–4354. doi: 10.1073/pnas.85.12.4350. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Baas F., Borst P. The tissue dependent expression of hamster P-glycoprotein genes. FEBS Lett. 1988 Mar 14;229(2):329–332. doi: 10.1016/0014-5793(88)81150-5. [DOI] [PubMed] [Google Scholar]
  5. Bear C. E., Li C. H., Kartner N., Bridges R. J., Jensen T. J., Ramjeesingh M., Riordan J. R. Purification and functional reconstitution of the cystic fibrosis transmembrane conductance regulator (CFTR). Cell. 1992 Feb 21;68(4):809–818. doi: 10.1016/0092-8674(92)90155-6. [DOI] [PubMed] [Google Scholar]
  6. Bradley G., Georges E., Ling V. Sex-dependent and independent expression of the P-glycoprotein isoforms in Chinese hamster. J Cell Physiol. 1990 Dec;145(3):398–408. doi: 10.1002/jcp.1041450303. [DOI] [PubMed] [Google Scholar]
  7. Chaudhary P. M., Roninson I. B. Expression and activity of P-glycoprotein, a multidrug efflux pump, in human hematopoietic stem cells. Cell. 1991 Jul 12;66(1):85–94. doi: 10.1016/0092-8674(91)90141-k. [DOI] [PubMed] [Google Scholar]
  8. Chen C. J., Chin J. E., Ueda K., Clark D. P., Pastan I., Gottesman M. M., Roninson I. B. Internal duplication and homology with bacterial transport proteins in the mdr1 (P-glycoprotein) gene from multidrug-resistant human cells. Cell. 1986 Nov 7;47(3):381–389. doi: 10.1016/0092-8674(86)90595-7. [DOI] [PubMed] [Google Scholar]
  9. Cheng S. H., Rich D. P., Marshall J., Gregory R. J., Welsh M. J., Smith A. E. Phosphorylation of the R domain by cAMP-dependent protein kinase regulates the CFTR chloride channel. Cell. 1991 Sep 6;66(5):1027–1036. doi: 10.1016/0092-8674(91)90446-6. [DOI] [PubMed] [Google Scholar]
  10. Chou J. L., Rozmahel R., Tsui L. C. Characterization of the promoter region of the cystic fibrosis transmembrane conductance regulator gene. J Biol Chem. 1991 Dec 25;266(36):24471–24476. [PubMed] [Google Scholar]
  11. Cordon-Cardo C., O'Brien J. P., Boccia J., Casals D., Bertino J. R., Melamed M. R. Expression of the multidrug resistance gene product (P-glycoprotein) in human normal and tumor tissues. J Histochem Cytochem. 1990 Sep;38(9):1277–1287. doi: 10.1177/38.9.1974900. [DOI] [PubMed] [Google Scholar]
  12. Cordon-Cardo C., O'Brien J. P., Casals D., Rittman-Grauer L., Biedler J. L., Melamed M. R., Bertino J. R. Multidrug-resistance gene (P-glycoprotein) is expressed by endothelial cells at blood-brain barrier sites. Proc Natl Acad Sci U S A. 1989 Jan;86(2):695–698. doi: 10.1073/pnas.86.2.695. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Crawford I., Maloney P. C., Zeitlin P. L., Guggino W. B., Hyde S. C., Turley H., Gatter K. C., Harris A., Higgins C. F. Immunocytochemical localization of the cystic fibrosis gene product CFTR. Proc Natl Acad Sci U S A. 1991 Oct 15;88(20):9262–9266. doi: 10.1073/pnas.88.20.9262. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Devault A., Gros P. Two members of the mouse mdr gene family confer multidrug resistance with overlapping but distinct drug specificities. Mol Cell Biol. 1990 Apr;10(4):1652–1663. doi: 10.1128/mcb.10.4.1652. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Endicott J. A., Ling V. The biochemistry of P-glycoprotein-mediated multidrug resistance. Annu Rev Biochem. 1989;58:137–171. doi: 10.1146/annurev.bi.58.070189.001033. [DOI] [PubMed] [Google Scholar]
  16. Endicott J. A., Sarangi F., Ling V. Complete cDNA sequences encoding the Chinese hamster P-glycoprotein gene family. DNA Seq. 1991;2(2):89–101. doi: 10.3109/10425179109039677. [DOI] [PubMed] [Google Scholar]
  17. Fojo A. T., Ueda K., Slamon D. J., Poplack D. G., Gottesman M. M., Pastan I. Expression of a multidrug-resistance gene in human tumors and tissues. Proc Natl Acad Sci U S A. 1987 Jan;84(1):265–269. doi: 10.1073/pnas.84.1.265. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Georges E., Bradley G., Gariepy J., Ling V. Detection of P-glycoprotein isoforms by gene-specific monoclonal antibodies. Proc Natl Acad Sci U S A. 1990 Jan;87(1):152–156. doi: 10.1073/pnas.87.1.152. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Gill D. R., Hyde S. C., Higgins C. F., Valverde M. A., Mintenig G. M., Sepúlveda F. V. Separation of drug transport and chloride channel functions of the human multidrug resistance P-glycoprotein. Cell. 1992 Oct 2;71(1):23–32. doi: 10.1016/0092-8674(92)90263-c. [DOI] [PubMed] [Google Scholar]
  20. Gottesman M. M., Pastan I. Resistance to multiple chemotherapeutic agents in human cancer cells. Trends Pharmacol Sci. 1988 Feb;9(2):54–58. doi: 10.1016/0165-6147(88)90117-4. [DOI] [PubMed] [Google Scholar]
  21. Gowen C. W., Jr, Gowen M. A., Knowles M. R. Colonic transepithelial potential difference in infants with cystic fibrosis. J Pediatr. 1991 Mar;118(3):412–415. doi: 10.1016/s0022-3476(05)82158-4. [DOI] [PubMed] [Google Scholar]
  22. Gray M. A., Greenwell J. R., Argent B. E. Secretin-regulated chloride channel on the apical plasma membrane of pancreatic duct cells. J Membr Biol. 1988 Oct;105(2):131–142. doi: 10.1007/BF02009166. [DOI] [PubMed] [Google Scholar]
  23. Gros P., Croop J., Housman D. Mammalian multidrug resistance gene: complete cDNA sequence indicates strong homology to bacterial transport proteins. Cell. 1986 Nov 7;47(3):371–380. doi: 10.1016/0092-8674(86)90594-5. [DOI] [PubMed] [Google Scholar]
  24. Gros P., Raymond M., Bell J., Housman D. Cloning and characterization of a second member of the mouse mdr gene family. Mol Cell Biol. 1988 Jul;8(7):2770–2778. doi: 10.1128/mcb.8.7.2770. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Hoffmann E. K., Simonsen L. O. Membrane mechanisms in volume and pH regulation in vertebrate cells. Physiol Rev. 1989 Apr;69(2):315–382. doi: 10.1152/physrev.1989.69.2.315. [DOI] [PubMed] [Google Scholar]
  26. Hsu S. I., Lothstein L., Horwitz S. B. Differential overexpression of three mdr gene family members in multidrug-resistant J774.2 mouse cells. Evidence that distinct P-glycoprotein precursors are encoded by unique mdr genes. J Biol Chem. 1989 Jul 15;264(20):12053–12062. [PubMed] [Google Scholar]
  27. Hyde S. C., Emsley P., Hartshorn M. J., Mimmack M. M., Gileadi U., Pearce S. R., Gallagher M. P., Gill D. R., Hubbard R. E., Higgins C. F. Structural model of ATP-binding proteins associated with cystic fibrosis, multidrug resistance and bacterial transport. Nature. 1990 Jul 26;346(6282):362–365. doi: 10.1038/346362a0. [DOI] [PubMed] [Google Scholar]
  28. LEBLOND C. P., CLERMONT Y. Definition of the stages of the cycle of the seminiferous epithelium in the rat. Ann N Y Acad Sci. 1952 Nov 20;55(4):548–573. doi: 10.1111/j.1749-6632.1952.tb26576.x. [DOI] [PubMed] [Google Scholar]
  29. MacLeod R. J., Hamilton J. R. Separate K+ and Cl- transport pathways are activated for regulatory volume decrease in jejunal villus cells. Am J Physiol. 1991 Mar;260(3 Pt 1):G405–G415. doi: 10.1152/ajpgi.1991.260.3.G405. [DOI] [PubMed] [Google Scholar]
  30. Marino C. R., Matovcik L. M., Gorelick F. S., Cohn J. A. Localization of the cystic fibrosis transmembrane conductance regulator in pancreas. J Clin Invest. 1991 Aug;88(2):712–716. doi: 10.1172/JCI115358. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Meyers M. B., Scotto K. W., Sirotnak F. M. P-glycoprotein content and mediation of vincristine efflux: correlation with the level of differentiation in luminal epithelium of mouse small intestine. Cancer Commun. 1991 May;3(5):159–165. doi: 10.3727/095535491820873335. [DOI] [PubMed] [Google Scholar]
  32. Noonan K. E., Beck C., Holzmayer T. A., Chin J. E., Wunder J. S., Andrulis I. L., Gazdar A. F., Willman C. L., Griffith B., Von Hoff D. D. Quantitative analysis of MDR1 (multidrug resistance) gene expression in human tumors by polymerase chain reaction. Proc Natl Acad Sci U S A. 1990 Sep;87(18):7160–7164. doi: 10.1073/pnas.87.18.7160. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. O'Brien J. A., Walters R. J., Sepúlveda F. V. Regulatory volume decrease in small intestinal crypts is inhibited by K+ and Cl- channel blockers. Biochim Biophys Acta. 1991 Dec 9;1070(2):501–504. doi: 10.1016/0005-2736(91)90093-n. [DOI] [PubMed] [Google Scholar]
  34. Quinton P. M. Cystic fibrosis: a disease in electrolyte transport. FASEB J. 1990 Jul;4(10):2709–2717. doi: 10.1096/fasebj.4.10.2197151. [DOI] [PubMed] [Google Scholar]
  35. Raymond M., Gros P. Mammalian multidrug-resistance gene: correlation of exon organization with structural domains and duplication of an ancestral gene. Proc Natl Acad Sci U S A. 1989 Sep;86(17):6488–6492. doi: 10.1073/pnas.86.17.6488. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Roberts R. M., Bazer F. W. The functions of uterine secretions. J Reprod Fertil. 1988 Mar;82(2):875–892. doi: 10.1530/jrf.0.0820875. [DOI] [PubMed] [Google Scholar]
  37. Sarkadi B., Cheung R., Mack E., Grinstein S., Gelfand E. W., Rothstein A. Cation and anion transport pathways in volume regulatory response of human lymphocytes to hyposmotic media. Am J Physiol. 1985 May;248(5 Pt 1):C480–C487. doi: 10.1152/ajpcell.1985.248.5.C480. [DOI] [PubMed] [Google Scholar]
  38. Sepúlveda F. V., Fargon F., McNaughton P. A. K+ and Cl- currents in enterocytes isolated from guinea-pig small intestinal villi. J Physiol. 1991 Mar;434:351–367. doi: 10.1113/jphysiol.1991.sp018474. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Silverman J. A., Raunio H., Gant T. W., Thorgeirsson S. S. Cloning and characterization of a member of the rat multidrug resistance (mdr) gene family. Gene. 1991 Oct 15;106(2):229–236. doi: 10.1016/0378-1119(91)90203-n. [DOI] [PubMed] [Google Scholar]
  40. Sinaasappel M., Veeze H. J., De Jonge H. R. New insights into the pathogenesis of cystic fibrosis. Scand J Gastroenterol Suppl. 1990;178:17–25. doi: 10.3109/00365529009093146. [DOI] [PubMed] [Google Scholar]
  41. Solc C. K., Wine J. J. Swelling-induced and depolarization-induced C1-channels in normal and cystic fibrosis epithelial cells. Am J Physiol. 1991 Oct;261(4 Pt 1):C658–C674. doi: 10.1152/ajpcell.1991.261.4.C658. [DOI] [PubMed] [Google Scholar]
  42. Sood R., Bear C., Auerbach W., Reyes E., Jensen T., Kartner N., Riordan J. R., Buchwald M. Regulation of CFTR expression and function during differentiation of intestinal epithelial cells. EMBO J. 1992 Jul;11(7):2487–2494. doi: 10.1002/j.1460-2075.1992.tb05313.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Sugawara I., Kataoka I., Morishita Y., Hamada H., Tsuruo T., Itoyama S., Mori S. Tissue distribution of P-glycoprotein encoded by a multidrug-resistant gene as revealed by a monoclonal antibody, MRK 16. Cancer Res. 1988 Apr 1;48(7):1926–1929. [PubMed] [Google Scholar]
  44. Thiebaut F., Tsuruo T., Hamada H., Gottesman M. M., Pastan I., Willingham M. C. Cellular localization of the multidrug-resistance gene product P-glycoprotein in normal human tissues. Proc Natl Acad Sci U S A. 1987 Nov;84(21):7735–7738. doi: 10.1073/pnas.84.21.7735. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Thiebaut F., Tsuruo T., Hamada H., Gottesman M. M., Pastan I., Willingham M. C. Immunohistochemical localization in normal tissues of different epitopes in the multidrug transport protein P170: evidence for localization in brain capillaries and crossreactivity of one antibody with a muscle protein. J Histochem Cytochem. 1989 Feb;37(2):159–164. doi: 10.1177/37.2.2463300. [DOI] [PubMed] [Google Scholar]
  46. Trezise A. E., Buchwald M. In vivo cell-specific expression of the cystic fibrosis transmembrane conductance regulator. Nature. 1991 Oct 3;353(6343):434–437. doi: 10.1038/353434a0. [DOI] [PubMed] [Google Scholar]
  47. Valverde M. A., Díaz M., Sepúlveda F. V., Gill D. R., Hyde S. C., Higgins C. F. Volume-regulated chloride channels associated with the human multidrug-resistance P-glycoprotein. Nature. 1992 Feb 27;355(6363):830–833. doi: 10.1038/355830a0. [DOI] [PubMed] [Google Scholar]
  48. Wagner J. A., Cozens A. L., Schulman H., Gruenert D. C., Stryer L., Gardner P. Activation of chloride channels in normal and cystic fibrosis airway epithelial cells by multifunctional calcium/calmodulin-dependent protein kinase. Nature. 1991 Feb 28;349(6312):793–796. doi: 10.1038/349793a0. [DOI] [PubMed] [Google Scholar]
  49. Yoshimura K., Nakamura H., Trapnell B. C., Dalemans W., Pavirani A., Lecocq J. P., Crystal R. G. The cystic fibrosis gene has a "housekeeping"-type promoter and is expressed at low levels in cells of epithelial origin. J Biol Chem. 1991 May 15;266(14):9140–9144. [PubMed] [Google Scholar]
  50. van der Bliek A. M., Kooiman P. M., Schneider C., Borst P. Sequence of mdr3 cDNA encoding a human P-glycoprotein. Gene. 1988 Nov 30;71(2):401–411. doi: 10.1016/0378-1119(88)90057-1. [DOI] [PubMed] [Google Scholar]

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