Abstract
P-glycoproteins can cause multidrug resistance in mammalian tumor cells by active extrusion of cytotoxic drugs. The natural function of these evolutionarily conserved, membrane-bound ATP binding transport proteins is unknown. In mammals, P-glycoproteins are abundantly present in organs associated with the digestive tract. We have studied the tissue-specific expression of Caenorhabditis elegans P-glycoprotein genes pgp-1 and pgp-3 by transformation of nematodes with pgp-lacZ gene fusion constructs in which the promoter area of the pgp genes was fused to the coding region of lacZ. Expression of pgp-1 and pgp-3, as inferred from pgp-lacZ transgenic nematodes, was confined to the intestinal cells. The expression patterns of both genes were virtually indistinguishable. Quantitative analysis of pgp mRNA levels during development showed that pgp-1, -2, and -3 were expressed throughout the life cycle of C.elegans, albeit with some variation indicating developmental regulation. The expression of P-glycoprotein genes in intestinal cells is an evolutionarily conserved feature of these genes, consistent with the hypothesis that P-glycoproteins provide a mechanism of protection against environmental toxins.
Full text
PDF





Images in this article
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Ames B. N., Profet M., Gold L. S. Dietary pesticides (99.99% all natural). Proc Natl Acad Sci U S A. 1990 Oct;87(19):7777–7781. doi: 10.1073/pnas.87.19.7777. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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]
- Chin J. E., Soffir R., Noonan K. E., Choi K., Roninson I. B. Structure and expression of the human MDR (P-glycoprotein) gene family. Mol Cell Biol. 1989 Sep;9(9):3808–3820. doi: 10.1128/mcb.9.9.3808. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Conrad R., Thomas J., Spieth J., Blumenthal T. Insertion of part of an intron into the 5' untranslated region of a Caenorhabditis elegans gene converts it into a trans-spliced gene. Mol Cell Biol. 1991 Apr;11(4):1921–1926. doi: 10.1128/mcb.11.4.1921. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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]
- Cox G. N., Kusch M., Edgar R. S. Cuticle of Caenorhabditis elegans: its isolation and partial characterization. J Cell Biol. 1981 Jul;90(1):7–17. doi: 10.1083/jcb.90.1.7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Croop J. M., Raymond M., Haber D., Devault A., Arceci R. J., Gros P., Housman D. E. The three mouse multidrug resistance (mdr) genes are expressed in a tissue-specific manner in normal mouse tissues. Mol Cell Biol. 1989 Mar;9(3):1346–1350. doi: 10.1128/mcb.9.3.1346. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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]
- Ellis H. M., Horvitz H. R. Genetic control of programmed cell death in the nematode C. elegans. Cell. 1986 Mar 28;44(6):817–829. doi: 10.1016/0092-8674(86)90004-8. [DOI] [PubMed] [Google Scholar]
- 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]
- Fire A., Harrison S. W., Dixon D. A modular set of lacZ fusion vectors for studying gene expression in Caenorhabditis elegans. Gene. 1990 Sep 14;93(2):189–198. doi: 10.1016/0378-1119(90)90224-f. [DOI] [PubMed] [Google Scholar]
- Fire A. Integrative transformation of Caenorhabditis elegans. EMBO J. 1986 Oct;5(10):2673–2680. doi: 10.1002/j.1460-2075.1986.tb04550.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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]
- Kramer J. M., French R. P., Park E. C., Johnson J. J. The Caenorhabditis elegans rol-6 gene, which interacts with the sqt-1 collagen gene to determine organismal morphology, encodes a collagen. Mol Cell Biol. 1990 May;10(5):2081–2089. doi: 10.1128/mcb.10.5.2081. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kuchler K., Sterne R. E., Thorner J. Saccharomyces cerevisiae STE6 gene product: a novel pathway for protein export in eukaryotic cells. EMBO J. 1989 Dec 20;8(13):3973–3984. doi: 10.1002/j.1460-2075.1989.tb08580.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lincke C. R., The I., van Groenigen M., Borst P. The P-glycoprotein gene family of Caenorhabditis elegans. Cloning and characterization of genomic and complementary DNA sequences. J Mol Biol. 1992 Nov 20;228(2):701–711. doi: 10.1016/0022-2836(92)90855-e. [DOI] [PubMed] [Google Scholar]
- McGrath J. P., Varshavsky A. The yeast STE6 gene encodes a homologue of the mammalian multidrug resistance P-glycoprotein. Nature. 1989 Aug 3;340(6232):400–404. doi: 10.1038/340400a0. [DOI] [PubMed] [Google Scholar]
- Mello C. C., Kramer J. M., Stinchcomb D., Ambros V. Efficient gene transfer in C.elegans: extrachromosomal maintenance and integration of transforming sequences. EMBO J. 1991 Dec;10(12):3959–3970. doi: 10.1002/j.1460-2075.1991.tb04966.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Schinkel A. H., Borst P. Multidrug resistance mediated by P-glycoproteins. Semin Cancer Biol. 1991 Aug;2(4):213–226. [PubMed] [Google Scholar]
- Schinkel A. H., Roelofs E. M., Borst P. Characterization of the human MDR3 P-glycoprotein and its recognition by P-glycoprotein-specific monoclonal antibodies. Cancer Res. 1991 May 15;51(10):2628–2635. [PubMed] [Google Scholar]
- Stinchcomb D. T., Shaw J. E., Carr S. H., Hirsh D. Extrachromosomal DNA transformation of Caenorhabditis elegans. Mol Cell Biol. 1985 Dec;5(12):3484–3496. doi: 10.1128/mcb.5.12.3484. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Stringham E. G., Dixon D. K., Jones D., Candido E. P. Temporal and spatial expression patterns of the small heat shock (hsp16) genes in transgenic Caenorhabditis elegans. Mol Biol Cell. 1992 Feb;3(2):221–233. doi: 10.1091/mbc.3.2.221. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sulston J. E., Horvitz H. R. Post-embryonic cell lineages of the nematode, Caenorhabditis elegans. Dev Biol. 1977 Mar;56(1):110–156. doi: 10.1016/0012-1606(77)90158-0. [DOI] [PubMed] [Google Scholar]
- Sulston J. E., Schierenberg E., White J. G., Thomson J. N. The embryonic cell lineage of the nematode Caenorhabditis elegans. Dev Biol. 1983 Nov;100(1):64–119. doi: 10.1016/0012-1606(83)90201-4. [DOI] [PubMed] [Google Scholar]
- 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]
- Way J. C., Chalfie M. The mec-3 gene of Caenorhabditis elegans requires its own product for maintained expression and is expressed in three neuronal cell types. Genes Dev. 1989 Dec;3(12A):1823–1833. doi: 10.1101/gad.3.12a.1823. [DOI] [PubMed] [Google Scholar]
- Yang C. P., Cohen D., Greenberger L. M., Hsu S. I., Horwitz S. B. Differential transport properties of two mdr gene products are distinguished by progesterone. J Biol Chem. 1990 Jun 25;265(18):10282–10288. [PubMed] [Google Scholar]
- Zinn K., DiMaio D., Maniatis T. Identification of two distinct regulatory regions adjacent to the human beta-interferon gene. Cell. 1983 Oct;34(3):865–879. doi: 10.1016/0092-8674(83)90544-5. [DOI] [PubMed] [Google Scholar]


