Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Ulcerative colitis and adenocarcinoma of the colon in Gαi2-deficient mice

Nature Genetics volume 10, pages 143–150 (1995)Cite this article

Abstract

G proteins are involved in cellular signalling and regulate a variety of biological processes including differentiation and development. We have generated mice deficient for the G protein subunit αi2 (Gαi2) by homologous recombination in embryonic stem cells. Gαi2–deficient mice display growth retardation and develop a lethal diffuse colitis with clinical and histopathological features closely resembling ulcerative colitis in humans, including the development of adenocarcinoma of the colon. Prior to clinical symptoms, the mice show profound alterations in thymocyte maturation and function. The study of these animals should provide important insights into the pathogenesis of ulcerative colitis as well as carcinogenesis.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Birnbaumer, L. Receptor-to-effector signaling through G proteins: roles for βγ dimers as well as for α subunits. Cell 71, 1069–1072 (1992).

    Article  CAS  Google Scholar 

  2. Montmayeur, J.-P. & Borrelli, E. Targeting of Gαi2 to the Golgi by alternative spliced carboxyl-terminal region. Science 263, 95–98 (1994).

    Article  CAS  Google Scholar 

  3. Simonds, W.F., Goldsmith, P.K., Codina, J., Unson, C.G. & Spiegel, A.M. GB mediates α2-adrenergic inhibition of adenylyl cyclase in platelet membranes: in situ identification with G C-terminal antibodies. Proc. natn. Acad. Sci. U.S.A. 86, 7809–7813 (1989).

    Article  CAS  Google Scholar 

  4. Wong, Y.H. et al. Mutant α subunits of Gi2 inhibit cyclic AMP accumulation. Nature 351, 63–65 (1991).

    Article  CAS  Google Scholar 

  5. Taussig, R., Iñiguez-Lluhi, J.A. & Gilman, A.G. Inhibition of adenylyl cyclase by Giα. Science 261, 218–221 (1993).

    Article  CAS  Google Scholar 

  6. Yatani, A., Codina, J., Sekura, R.D., Birnbaumer, L. & Brown, A.M. Reconstitution of somatostatin and muscarinic receptor mediated stimulation of K+ channels by isolated Gk protein in clonal rat anterior pituitary cell membranes. Molec. Endocrinol. 1, 283–289 (1987).

    Article  CAS  Google Scholar 

  7. Yatani, A. et al. The G protein-gated atrial K+ channel is stimulated by three distinct G,α-subunits. Nature 336, 680–682 (1988).

    Article  CAS  Google Scholar 

  8. Kirsch, G., Codina, J., Birnbaumer, L. & Brown, A.M. Coupling of ATP-sensitive K+ channels to purinergic receptors by G-Proteins in rat ventricular myocytes. Am. J. Physiol. 259, H820–H826 (1990).

    CAS  PubMed  Google Scholar 

  9. Hermouet, S., Merendino, J.J., Gutkind, J.S. & Spiegel, A.M. Activating and inactivating mutations of the α subunit of Gi2 protein have opposite effects on proliferation of NIH 3T3 cells. Proc. natn. Acad. Sci. U.S.A. 88, 10455–10459 (1991).

    Article  CAS  Google Scholar 

  10. Gupta, S.K., Gallego, C., Johnson, G. & Heasley, L.E. MAP kinase is constitutively activated in gip2 and src transformed Rat-1 a fibroblasts. J. biol. Chem. 267, 7987–7990 (1992).

    CAS  Google Scholar 

  11. Watkins, D.C., Johnson, G.L. & Malbon, C.C. Regulation of the differentiation of teratocarcinoma cells into primitive endoderm by Gαi2. Science 258, 1373–1375 (1992).

    Article  CAS  Google Scholar 

  12. Moxham, C.M., Hod, Y. & Malbon, C.C. Induction of Gαi2-specific antisense RNA in vivo inhibits neonatal growth. Science 260, 991–995 (1993).

    Article  CAS  Google Scholar 

  13. Pace, A.M., Wong, Y.H. & Bourne, H.R. A mutant α subunit of Gi2 induced neoplastic transformation of Rat-1 cells. Proc. natn. Acad. Sci. U.S.A. 88, 7031–7035 (1991).

    Article  CAS  Google Scholar 

  14. Lyons, J. et al. Two G protein oncogenes in human endocrine tumours. Science 249, 655–659 (1990).

    Article  CAS  Google Scholar 

  15. Noel, J.P., Hamm, H.E. & Sigler, P.B. The 2.2Å crystal structure of transducin-α complexed with GTPgS. Nature 366, 654–663 (1994).

    Article  Google Scholar 

  16. Rudolph, U., Brabet, P., Hasty, P., Bradley, A. & Birnbaumer, L. Disruption of the Gi2α locus in embryonic stem cells and mice: a modified hit and run strategy with detection by a PCR dependent on gap repair. Transgenic Res. 2, 345–355 (1993).

    Article  CAS  Google Scholar 

  17. Fischer, M. et al. Cytokine production by mature and immature thymocytes. J. Immunol. 146, 3452–3456 (1991).

    CAS  PubMed  Google Scholar 

  18. Elson, C.O., Ealding, W. & Lefkowitz, J. A lavage technique allowing repeated measurement of IgA antibody in mouse intestinal secretions. J. Immunol. Meth. 67, 101–108 (1984).

    Article  CAS  Google Scholar 

  19. Schreiber, S., Raedler, A., Stenson, W.F. & MacDermott, R.P. The role of the mucosal immune system in inflammatory bowel disease. Gastroenterol. Clin. North Am. 21, 451–502 (1992).

    CAS  PubMed  Google Scholar 

  20. Sadlack, B. et al. Ulcerative colitis-like disease in mice with a disrupted interleukin-2 gene. Cell 75, 253–261 (1993).

    Article  CAS  Google Scholar 

  21. Kühn, R., Löhler, J., Rennick, D., Rajewsky, K. & MüIIer, W. lnterleukin-10-deficient mice develop chronic enterocolitis. Cell 75, 263–274 (1993).

    Article  Google Scholar 

  22. Mombaerts, P. et al. Spontaneous development of inflammatory bowel disease in T cell receptor mutant mice. Cell 75, 275–282 (1993).

    Article  CAS  Google Scholar 

  23. Morrissey, P.J., Charrier, K., Braddy, S., Liggitt, D. & Watson, J.D. CD4+T cells that express high levels of CD45RB induce wasting disease when transferred into congenic severe combined immunodeficiency mice.Disease development is prevented by cotransfer of purified CD4+ T cells. J. exp. Med. 178, 237–244 (1993).

    Article  CAS  Google Scholar 

  24. Powrie, F. et al. Inhibition of Th1 responses prevents inflammatory bowel disease in scid mice reconstituted with CD45RBhl CD4+ T cells. Immunity 1, 553–562 (1994).

    Article  CAS  Google Scholar 

  25. Chaffin, K.E. et al. Dissection of thymocyte signaling pathways by in vivo expression of pertussis toxin ADP-ribosyltransferase. EMBO J. 9, 3821–3829 (1990).

    Article  CAS  Google Scholar 

  26. Chaffin, K.E. & Perlmutter, R.M. A pertussis toxin-sensitive process controls thymocyte emigration. Eur. J. Immunol. 21, 2565–2573 (1991).

    Article  CAS  Google Scholar 

  27. Bargatze, R.F. & Butcher, E.C. Rapid G protein-regulated activation event involved in lymphocyte binding to high endothelial venules. J. exp. Med. 178, 367–372 (1993).

    Article  CAS  Google Scholar 

  28. Gupta, S.K. et al. Analysis of the fibroblast transformation potential of GTPase-deficient gip2 oncogenes. Mol. cell. Biol. 12, 190–197 (1992).

    Article  CAS  Google Scholar 

  29. Hsu, W.H. et al. Molecular cloning of a novel splice variant of the α subunit of the mammalian G0 protein. J. biol. Chem. 265, 11220–11226 (1990).

    CAS  PubMed  Google Scholar 

  30. Codina, J., Grenet, D., Chang, K.-J. & Birnbaumer, L., Gradient/SDS-PAGE: a useful tool in the investigation of signal transducing G proteins. J. Recept. Res. 11, 587–601 (1991).

    Article  CAS  Google Scholar 

  31. Scherer, N.M., Toro, M.-J., Entman, M.L. & Birnbaumer, L. G protein distribution in canine cardiac sarcoplasmatic reticulum and sarcolemma.Comparison to rabbit sceletal membranes and brain and erythrocyte G proteins. Arch. Biochem. Biophys. 259, 431–440 (1987).

    Article  CAS  Google Scholar 

Download references

Author information

Author notes

  1. Uwe Rudolph

    Present address: Institute of Pharmacology, University of Zürich, Winterthurerstrasse 190, Zürich, CH-8057, Switzerland

  2. Philippe Brabet

    Present address: Centre CNRS-INSERM de Pharmacologie-Endocrinologie, Rue de la Cardonille, 34094, Montpellier, Cedex 2, France

  3. Guylain Boulay & Lutz Birnbaumer

    Present address: Department of Anesthesiology, UCLA School of Medicine, Center for the Health Sciences, 10833 Le Conte Avenue, Los Angeles, California, 90095-1778, USA

Authors and Affiliations

  1. Departments of Cell Biology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas, 77030, USA

    Uwe Rudolph, Yogambal Srinivasan, Philippe Brabet, Guylain Boulay & Lutz Birnbaumer

  2. Department of Pharmacology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas, 77030, USA

    Uwe Rudolph

  3. Department of Pathology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas, 77030, USA

    Milton J. Finegold

  4. Department of Microbiology & Immunology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas, 77030, USA

    Susan S. Rich

  5. Department of Medicine, Baylor College of Medicine, One Baylor Plaza, Houston, Texas, 77030, USA

    Gregory R. Harriman & Lutz Birnbaumer

  6. Department of Molecular Physiology & Biophysics, Baylor College of Medicine, One Baylor Plaza, Houston, Texas, 77030, USA

    Lutz Birnbaumer

  7. Department of Division of Neuroscience, Baylor College of Medicine, One Baylor Plaza, Houston, Texas, 77030, USA

    Lutz Birnbaumer

  8. Department of Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, Texas, 77030, USA

    Allan Bradley

  9. Department of Howard Hughes Medical Institute, Baylor College of Medicine, One Baylor Plaza, Houston, Texas, 77030, USA

    Allan Bradley

Authors
  1. Uwe Rudolph
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Milton J. Finegold
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Susan S. Rich
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Gregory R. Harriman
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yogambal Srinivasan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Philippe Brabet
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Guylain Boulay
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Allan Bradley
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Lutz Birnbaumer
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rudolph, U., Finegold, M., Rich, S. et al. Ulcerative colitis and adenocarcinoma of the colon in Gαi2-deficient mice. Nat Genet 10, 143–150 (1995). https://doi.org/10.1038/ng0695-143

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng0695-143

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing