Abstract
A new haplotype of the β-glucuronidase gene complex, [Gus]N, has been characterized following its transfer from the PAC/Cr strain to the standard strain C57BL/6J. TheN haplotype contains a novel structural gene allele which encodes an allozyme differing from all previously characterized allozymes in both size and charge. Altered systemic regulation is exhibited by the [Gus]N haplotype. Multiple tissues contain levels of GUS protein that are 60±15% those found in the standardB haplotype. The regulatory mechanism for reduction is complex, involving tissue-specific changes in both enzyme synthesis and enzyme turnover. The changes in GUS protein synthesis do not result from changes in GUS mRNA levels. Instead, the amount of mature enzyme formed per mRNA molecule, or translational yield, is altered. These regulatory changes parallel those seen in other systemic regulatory variants of GUS which are also altered in translational yield. A commonality of mechanism among systemic regulatory variants of this gene is suggested. TheN haplotype is also exceptional in the nature of its response to androgenic induction in kidney proximal tubule epithelial cells. The time course for GUS induction consists of a lag period followed by a progressive increase in mRNA, rate of enzyme synthesis, and enzyme activity. For the [Gus]N haplotype the lag is of an exceptionally short duration and the plateau is of a greater magnitude than for any haplotype previously described.
Similar content being viewed by others
References
Almagor, H., and Paigen, K. (1988). Chemical kinetics of induced gene expression: Activation of transcription by noncooperative binding of multiple regulatory molecules.Biochemistry 272094.
Berger, F. G., Gross, K. W., and Watson, G. (1981). Isolation and characterization of a DNA sequence complementary to an androgen-inducible messenger RNA from mouse kidney.J. Biol. Chem. 2567006.
Berger, F. G., Szymanski, P., Read, E., and Watson, G. (1984). Androgen-regulated ornithine decarboxylase mRNAs of mouse kidney.J. Biol. Chem. 2597941.
Berger, F. G., Loose, D., Meisner, H., and Watson, G. (1986). Androgen induction of messenger RNA concentrations in mouse kidney is posttranscriptional.Biochemistry 251170.
Bracey, L. T., and Paigen, K. (1987). Changes in translational yield regulate tissue-specific expression of β-glucuronidase.Proc. Natl. Acad. Sci. USA 849020.
Bullock, L. P., Watson, G., and Paigen, K. (1985). Weak androgen reduces the rate constant of β-glucuronidase induction.Mol. Cell. Endocrinol. 41179.
Cox, R. A. (1968). The use of guanidinium chloride in the isolation of nucleic acids.Methods Enzymol. 12B120.
Fishman, W. H. (1951). β-Glucuronidase and the action of steroid hormones.Ann. N.Y. Acad. Sci. 54548.
Fishman, W. H., Goldman, S. S., and DeLellis, R. (1967). Dual localization of β-glucuronidase in endoplasmic reticulum and in lysosomes.Nature 213457.
Gan, J. C., and Jeffay, H. (1967). Origins and metabolism of the intracellular amino acid pools in rat liver and muscle.Biochim. Biophys. Acta 148448.
Ganschow, R., and Paigen, K. (1967). Separate genes determining the structure and intracellular location of hepatic glucuronidase.Proc. Natl. Acad. Sci. Wash. 58938.
Hayashi, M., Nakajima, Y., and Fishman, W. H. (1964). The cytologic demonstration of β-glucuronidase employing naphthol AS-BI glucuronide and hexazonium pararosanilin; a preliminary report.J. Histochem. Cytochem. 12293.
Labarca, C., and Paigen, K. (1977). mRNA-directed synthesis of cataytically active mouse β-glucuronidase inXenopus oocytes.Proc. Natl. Acad. Sci. USA 744462.
Laemmli, U. K. (1970). Cleavage of structural proteins during the assembly of the head of bacteriophage T4.Nature 227680.
Lalley, P. A., and Shows, T. B. (1974). Lysosomal and microsomal glucuronidase: Genetic variant alters electrophoretic mobility of both hydrolases.Science 185442.
Lin, C. W. (1975). Multiple forms of beta-glucuronidase: Molecular nature, transformation, and subcellular translocation. In Markert, D. L. (ed.),Isozymes Academic Press, New York, p. 637.
Loftfield, R. B., and Harris, A. J. (1956). Participation of free amino acids in protein synthesis.J. Biol. Chem. 219151.
Lusis, A. J., and Paigen, K. (1978). The large isolation of mouse β-glucuronidase and comparison of allozymes.J. Biol. Chem. 2537336.
Lusis, A. J., Chapman, V. M., Wagenstein, R. W., and Paigen, K. (1983). Trans-acting temporal locus within theβ-glucuronidase gene complex.Proc. Natl. Acad. Sci. USA 804398.
Maniatis, T., Fritsch, E. F., and Sambrook, J. (1982). Electrophoresis of RNA through gels containing formadehyde. InMolecular Cloning. A Laboratory Manual Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y., p. 203.
Owens, J. W., Gammon, K. L., and Stahl, P. D. (1975). Multiple forms of β-glucuronidase in rat liver lysosomes and microsomes.Arch. Biochem. Biophys. 166258.
Owerbach, D., and Lusis, A. J. (1976). Phenobarbital induction of egasyn: Availability of egasynin vivo determines glucuronidase binding to membrane.Biochem. Biophys. Res. Commun. 69628.
Paigen, K. (1961). The effect of mutation on the intracellular location of β-glucuronidase.Exp. Cell Res. 25286.
Paigen, K. (1979). Acid hydrolases as models of genetic control.Annu. Rev. Genet. 13417.
Paigen, K., and Noell, W. K. (1961). Two linked genes showing a similar timing of expression in mice.Nature 190148.
Palmer, R., Gallagher, P. M., Boyko, W. L., and Ganschow, R. E. (1983). Genetic control of levels of murine kidney glucuronidase mRNA in response to androgen.Proc. Natl. Acad. Sci. USA 807596.
Pfister, K., Paigen, K., Watson, G., and Chapman, V. (1982). Expression of β-glucuronidase haplotypes in prototype and congenic mouse strains.Biochem. Genet. 20519.
Pfister, K., Watson, G., Chapman, V., and Paigen, K. (1984). Kinetics of β-glucuronidase induction by androgen.J. Biol. Chem. 2595816.
Pfister, K., Chapman, V., Watson, G., and Paigen, K. (1985). Genetic variation for enzyme structure and systemic regulation in two new haplotypes of the β-glucuronidase gene ofMus musculus castaneus.J. Biol. Chem. 26011588.
Price, V. E., Sterling, W. R., Tarantola, V. A., Hartley, R. W., and Rechcigl, M., Jr. (1962). The kinetics of catalase synthesis and destructionin vivo.J. Biol. Chem. 2373468.
Schimke, R. T., and Doyle, D. (1970). Control of enzyme levels in animals tissues.Annu. Rev. Biochem. 39929.
Schimke, R. T., Sweeney, E. W., and Berlin, C. M. (1964). An analysis of the kinetics of rat liver tryptophan pyrrolase induction: The significance of both enzyme synthesis and degradation.Biochem. Biophys. Res. Commun. 15214.
Segal, H. L., and Kim, Y. S. (1965). Environmental control of enzyme synthesis and degradation.J. Cell. Comp. Physiol. 6611.
Sidman, R. L., and Green, M. C. (1965). Retinal degeneration in the mouse. Location of therd locus in linkage group XVII.J. Hered. 5623.
Smith, K., and Ganschow, R. E. (1978). Turnover of murine β-glucuronidase. Comparison among liver, kidney, and spleen and between lysosomes and microsomes.J. Biol. Chem. 2535437.
Swank, R. T., and Paigen, K. (1973). Biochemical and genetic evidence for a macromolecular β-glucuronidase complex in microsomal membranes.J. Mol. Biol. 77371.
Swank, R. T., Paigen, K., and Ganschow, R. E. (1973). Genetic control of glucuronidase induction in mice.J. Mol. Biol. 81225.
Swank, R. T., Paigen, K., Davey, R., Chapman, V., Labarca, C., Watson, G., Ganschow, R., Brandt, E. J., and Novak, E. (1978). Genetic regulation of mammalian glucuronidase.Recent Prog. Horm. Res. 34401.
Swank, R. T., Moore, K., and Chapman, V. M. (1987). Abnormal subcellular distribution of β-glucuronidase in mice with a genetic alteration in enzyme structure.Biochem. Genet. 25161.
Tomino, S., Paigen, K., Tulsiani, T. R. P., and Touster, O. (1975). Purification and chemical properties of mouse liver lysosomal (L) β-glucuronidase.J. Biol. Chem. 2508503.
Watson, C. S., and Catterall, J. F. (1986). Genetic regulation of androgen-induced accumulation of mouse renal β-glucuronidase messenger ribonucleic acid.Endrocrinology 1181081.
Watson, G., and Paigen, K. (1978). Segregation of genetic determinants for murine glucuronidase synthesis and loss in CXB recombinant-inbred strains.Biochem. Genet. 16897.
Watson, G., and Paigen, K. (1987). Genetic variation in kinetic constants that describe β-glucuronidase and mRNA induction in androgen-treated mice.Mol. Cell. Biol. 71085.
Watson, G., Davey, R. A., Labarca, C., and Paigen, K. (1981). Genetic determination of kinetic parameters in β-glucuronidase induction by androgen.J. Biol. Chem. 2563005.
Watson, G., Felder, M., Rabinow, L., Moore, K., Labarca, C., Tietze, C., Vander Molen, G., Bracey, L., Brabant, M., Cai, J., and Paigen, K. (1985). Properties of rat and mouse β-glucuronidase mRNA and cDNA, including evidence of sequence polymorphism and genetic regulation of mRNA levels.Gene 3615.
Author information
Authors and Affiliations
Additional information
This work was supported by United States Health Service Research Grant GM 31656.
Rights and permissions
About this article
Cite this article
Bracey, L.T., Paigen, K. TheN haplotype of the murineβ-glucuronidase gene is altered in both its systemic regulation and its response to androgen induction. Biochem Genet 27, 1–15 (1989). https://doi.org/10.1007/BF00563014
Received:
Revised:
Issue Date:
DOI: https://doi.org/10.1007/BF00563014