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G Proteins Regulating Insulin Action and Obesity

Analysis by Conditional, Targeted Expression of Antisense RNA in vivo

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Book cover G Proteins, Receptors, and Disease

Part of the book series: Contemporary Endocrinology ((COE,volume 6))

Abstract

This chapter introduces a novel approach to the study of G-protein function in vivo in which transgenic mice are created that harbor α conditional, tissue-specific expression vector that can produce RNA antisense to target mRNA(s). The central role of G proteins in transmembrane signaling from the superfamily of G-protein-linked receptors (GPLRs) to a less populous class of effector molecules that includes adenyl cyclase, phospholipase C (PLC), and various ion channels needs little explanation (see earlier review articles 1–10). Much less obvious is the pivotal role G proteins play in more complex biological processes, such as growth and development. Infectious diseases such as cholera and whooping cough, for example, express elements of their pathology via covalent modification (mono-adenosine diphosphate [ADP]-ribosylation) of G-protein targets. In endocrine tissues, mutations of specific G-protein subunits have been shown to induce tumor growth (11). Finally, genetic mutations of G proteins have been linked to pseudo-hypoparathyroidism, McCune-Albright syndrome (MAS), and Albright’s hereditary osteodystrophy in humans (12).

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Reference

  1. Gilman AG. G proteins: transducers of receptor-generated signals. Annu Rev Biochem 1987;56:615–649.

    Article  PubMed  CAS  Google Scholar 

  2. Johnson G, Dhanasekaran N. The G-protein family and their interaction with receptors. Endocr Rev 1989;10:317–331.

    Article  PubMed  CAS  Google Scholar 

  3. Bourne HR, Sanders DA, McCormick F. The GTPase superfamily: a conserved switch for diverse cell functions. Nature 1990;348:125–132.

    Article  PubMed  CAS  Google Scholar 

  4. Birnbaumer L, Abramowitz J, Brown AM. Receptor-effector coupling by G proteins. Biochim Biophysics Acta 1990;1031:163–224.

    Article  CAS  Google Scholar 

  5. Kaziro Y, Itoh H, Kozasa T, Nakafuku M, Satoh, T. Structure and function of signal-transducing GTP-binding proteins. Annu Rev Biochem 1991;60:349–400.

    Article  PubMed  CAS  Google Scholar 

  6. Bourne HR, Sanders DA, McCormick F. The GTPase superfamily: conserved structure and molecular mechanism. Nature 1991;349:117–127.

    Article  PubMed  CAS  Google Scholar 

  7. Simon MI, Strathmann MP, Gautam N. Diversity of G proteins in signal transduction. Science 1991;252:802–808.

    Article  PubMed  CAS  Google Scholar 

  8. Hadcock JR, Malbon CC. Regulation of receptor expression by agonist: transcriptional and post-transcriptional controls. Trends Neurosci 1991;14:242–247.

    Article  PubMed  CAS  Google Scholar 

  9. Hepler JR, Gilman AG. G proteins. Trends Biochem. Sci. 1992;17:383–387.

    Article  PubMed  CAS  Google Scholar 

  10. Clapham DE, Neer EJ. New roles for G protein β/γ dimers in transmembrane signalling. Nature 1993;365:403–406.

    Article  PubMed  CAS  Google Scholar 

  11. Lyons J, Landis CA, Harsh G, Vallar L, Grunewald K, Feichtinger H, Duh QY, Clark OH, Kawasaki E, Bourne HR, and McCormick F. Two G protein oncogenes in human endocrine tumors. Science 1990;249:655–659.

    Article  PubMed  CAS  Google Scholar 

  12. Milligan G, Wakelam M. (eds). G-proteins, Signal Transduction and Disease. Academic, New York, 1992.

    Google Scholar 

  13. Moxham CM, Hod Y, Malbon CC. Induction of Giα2-specific antisense RNA in vivo inhibits neonatal growth. Science 1993;260:991–995.

    Article  PubMed  CAS  Google Scholar 

  14. Moxham CM, Hod Y, and Malbon CC. Giα2 mediates the inhibitory regulation of adenylylcyclase in vivo: analysis in transgenic mice with Giα2 suppressed by inducible antisense RNA. Dev Genet 1993;14:266–273.

    Article  PubMed  CAS  Google Scholar 

  15. Rudolph U, Finegold MJ, Rich SS, Harriman GR, Srinivasan Y, Brabet G, Bradley A, and Birnbaumer, L. Ulcerative colitis and adenocarcinoma of the colon in Giα2-deficient mice. Nat Genet 1995;10:143–150.

    Article  PubMed  CAS  Google Scholar 

  16. Watkins DC, Johnson GL, and Malbon CC. Giα2 regulates differentiation of stem cells to primitive endoderm in F9 teratocarcinoma cells. Science 1992;258:1373–1375.

    Article  PubMed  CAS  Google Scholar 

  17. Gao P, Watkins DC, and Malbon CC. Expression of constitutively-active mutant Gsα (G225T) or of a null-mutant of Giα2 (G203T) induce differentiation of teratocarcinoma stem cells to primitive endoderm. Am J Physiol 1995;268:C1460–C1466.

    PubMed  CAS  Google Scholar 

  18. Gao P, Malbon CC. Giα2 regulates stem cell differentiation via phospholipase C and MAP kinase pathways. J Biol Chem, 1996;271:9002–9009.

    Article  PubMed  CAS  Google Scholar 

  19. Gao P, Malbon CC. Differentiation of F9 teratocarcinoma stem cells to primitive endoderm is regulated by the Giα2/Gsα axis via phospholipase C and not adenylylcyclase. J Biol Chem 1996;271:30692–30698.

    Article  PubMed  CAS  Google Scholar 

  20. Strittmater SM, Valenzuela D, Kennedy TE, Neer EJ, and Fishman MC. Goα is a major growth cone protein subject to regulation by GAP-43. Nature 1990;344:836–841.

    Article  Google Scholar 

  21. Igarashi M, Strittmater SM, Vartanen H, and Fishman MC. Mediation by G-proteins of signals that cause collapse of growth cones. Science 1993;259:77–79.

    Article  PubMed  CAS  Google Scholar 

  22. Wang H-Y, Watkins DC, Malbon CC. Antisense oligodeoxynucleotides to Gs protein α-subunit sequence accelerate differentiation of fibroblasts to adipocytes. Nature 1992;358:334–337.

    Article  PubMed  CAS  Google Scholar 

  23. Su H-L, Malbon CC, and Wang H-Y. Increased expression of Giα2 in mouse embryo fibroblast 3T3-L1 cells promotes terminal differentiation to adipocytes. Am J Physiol 1993;34:C1729–C1735.

    Google Scholar 

  24. Wang H-Y, and Malbon CC. The Gsα/Giα2 axis controls adipogeneisis independently of adenylyl-cyclase. Int J Obes 1995;19:197–203.

    Google Scholar 

  25. Wang H-Y, Johnson GL, and Malbon CC. Gsα and adipogenesis: analysis of regulation using Gsα/Giα2 chimeric α-subunit expression. J Biol Chem 1996;271:22022–22029.

    Article  PubMed  CAS  Google Scholar 

  26. Haseloff J, and Gerlach WL. Dominant-negative control of gene expression. Nature 1988;334:585–591.

    Article  PubMed  CAS  Google Scholar 

  27. Miller PS. Effects of a trinucleotide ethyl phosphotriester, Gmp(Et)Gm p(Et)U, on mammalian cells in culture. Biochemistry 1989;16:1988–1996.

    Article  Google Scholar 

  28. Crooke ST, Bennett CF. Progress in antisense therapeutics. Ann Rev Pharmacol Toxicol 1996;36:107–129

    Article  CAS  Google Scholar 

  29. Agrawal S, (ed.). Antisense therapeutics. Humana, Totowa, NJ, 1996.

    Google Scholar 

  30. Kleuss C, Scherubl H, Hescheler J, Schultz G, and Wittig B. Different β-subunits determine G-protein interaction with transmembrane receptors. Nature 1992;358:424–426.

    Article  PubMed  CAS  Google Scholar 

  31. Kleuss C, Scherubl H, Hescheler J, Schultz G, and Wittig B. Selectivity in signal transduction determined by γ-subunits of heterotrimeric G proteins. Science 1993;259:832–843.

    Article  PubMed  CAS  Google Scholar 

  32. Moxham CM, and Malbon CC. Insulin action impaired by deficiency of the G-protein Gi α 2. Nature 1996;379:840–845.

    Article  PubMed  CAS  Google Scholar 

  33. White MF, Kahn CR. The insulin signaling system. J Biol Chem 1994;269:1–4.

    PubMed  CAS  Google Scholar 

  34. Reaven GM. Pathophysiology of insulin resistance in human disease. Physiol Rev 1995;75:473–486.

    PubMed  CAS  Google Scholar 

  35. Chen JF, Guo JH, Moxham CM, Wang, H-Y, and Malbon CC. Conditional, tissue-specific expression of Q205L Gi α 2 in vivo mimics insulin action. J Mol Med 1997;75:283–289.

    Article  PubMed  CAS  Google Scholar 

  36. Galvin-Parton PA, Chen X, Moxham CM, and Malbon CC. Induction of G α q-specific antisense RNA in vivo causes increased body mass and hyperadiposity. J Biol Chem 1997;272:4335–4341.

    Article  PubMed  CAS  Google Scholar 

  37. Weinstein LS, Shenker A, Gejman PV, Merino MJ, Friedman E, and Spiegel AM. Activating mutations of the stimulatory G protein in the McCune Albright syndrome. N Engl J Med 1991;325:1688–1695.

    Article  PubMed  CAS  Google Scholar 

  38. Schwindinger WF, Francomano CA, and Levine MA. Identification of a mutation in the gene encoding the alpha subunit of the stimulatory G protein of adenylyl cyclase in McCune-Albright syndrome. Proc Natl Acad Sci USA 1992;89:5152–5156.

    Article  PubMed  CAS  Google Scholar 

  39. Schnabel P, and Bohm M. Mutations of signal-transducing G proteins in human disease. J Mol Med 1995;73:221–228.

    Article  PubMed  CAS  Google Scholar 

  40. Shenker A, Weinstein LS, Moran A, Pescovitz OH, Charest NJ, Boney CM, Van Wyk JJ, Merino MJ, Feuillan PP, and Spiegel AM. Severe endocrine and non-endocrine manifestations of the McCune-Albright syndrome associated with activating mutations of stimulatory G protein Gs. J Pediatr 1993;123:509–518.

    Article  PubMed  CAS  Google Scholar 

  41. Fields S, and Sternglanz R. The two-hybrid system: an assay for protein-protein interactions. Trends Genet 1994;10:286–292.

    Article  PubMed  CAS  Google Scholar 

  42. Hatzoglou M, Lamers W, Bosch F, Wynshaw-Boris A, Clapp DW, Hanson RW. Hepatic gene transfer in animals using retroviruses containing the promoter from the gene for phsophoenolpyruvate carboxykinase. J Biol Chem 1990;265:17285–17293.

    PubMed  CAS  Google Scholar 

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Authors
  1. Craig C. Malbon PhD
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  2. Patricia Galvin-Parton MD
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  3. Hsien-yu Wang PhD
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  4. Christopher M. Moxham PhD
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Editor information

Editors and Affiliations

  1. National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA

    Allen M. Spiegel MD (Chief, Metabolic Diseases Branch) (Chief, Metabolic Diseases Branch)

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© 1998 Springer Science+Business Media New York

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Malbon, C.C., Galvin-Parton, P., Wang, Hy., Moxham, C.M. (1998). G Proteins Regulating Insulin Action and Obesity. In: Spiegel, A.M. (eds) G Proteins, Receptors, and Disease. Contemporary Endocrinology, vol 6. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-4612-1802-9_5

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  • DOI: https://doi.org/10.1007/978-1-4612-1802-9_5

  • Publisher Name: Humana Press, Totowa, NJ

  • Print ISBN: 978-1-4612-7290-8

  • Online ISBN: 978-1-4612-1802-9

  • eBook Packages: Springer Book Archive

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