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RGS6 as a Novel Therapeutic Target in CNS Diseases and Cancer

  • Review Article
  • Theme: Heterotrimeric G Protein-based Drug Development: Beyond Simple Receptor Ligands
  • Published:
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Abstract

Regulator of G protein signaling (RGS) proteins are gatekeepers regulating the cellular responses induced by G protein-coupled receptor (GPCR)-mediated activation of heterotrimeric G proteins. Specifically, RGS proteins determine the magnitude and duration of GPCR signaling by acting as a GTPase-activating protein for Gα subunits, an activity facilitated by their semiconserved RGS domain. The R7 subfamily of RGS proteins is distinguished by two unique domains, DEP/DHEX and GGL, which mediate membrane targeting and stability of these proteins. RGS6, a member of the R7 subfamily, has been shown to specifically modulate Gαi/o protein activity which is critically important in the central nervous system (CNS) for neuronal responses to a wide array of neurotransmitters. As such, RGS6 has been implicated in several CNS pathologies associated with altered neurotransmission, including the following: alcoholism, anxiety/depression, and Parkinson’s disease. In addition, unlike other members of the R7 subfamily, RGS6 has been shown to regulate G protein-independent signaling mechanisms which appear to promote both apoptotic and growth-suppressive pathways that are important in its tumor suppressor function in breast and possibly other tissues. Further highlighting the importance of RGS6 as a target in cancer, RGS6 mediates the chemotherapeutic actions of doxorubicin and blocks reticular activating system (Ras)-induced cellular transformation by promoting degradation of DNA (cytosine-5)-methyltransferase 1 (DNMT1) to prevent its silencing of pro-apoptotic and tumor suppressor genes. Together, these findings demonstrate the critical role of RGS6 in regulating both G protein-dependent CNS pathology and G protein-independent cancer pathology implicating RGS6 as a novel therapeutic target.

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References

  1. Chung KY. Structural aspects of GPCR-G protein coupling. Toxicol Res. 2013;29(3):149–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Gilman AG. G proteins: transducers of receptor-generated signals. Annu Rev Biochem. 1987;56:615–49.

    Article  CAS  PubMed  Google Scholar 

  3. Berman DM, Wilkie TM, Gilman AG. GAIP and RGS4 are GTPase-activating proteins for the Gi subfamily of G protein alpha subunits. Cell. 1996;86(3):445–52.

    Article  CAS  PubMed  Google Scholar 

  4. Dohlman HG, Thorner J. RGS proteins and signaling by heterotrimeric G proteins. J Biol Chem. 1997;272(7):3871–4.

    Article  CAS  PubMed  Google Scholar 

  5. Hepler JR, Berman DM, Gilman AG, Kozasa T. RGS4 and GAIP are GTPase-activating proteins for Gq alpha and block activation of phospholipase C beta by gamma-thio-GTP-Gq alpha. Proc Natl Acad Sci U S A. 1997;94(2):428–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Ross EM, Wilkie TM. GTPase-activating proteins for heterotrimeric G proteins: regulators of G protein signaling (RGS) and RGS-like proteins. Annu Rev Biochem. 2000;69:795–827.

    Article  CAS  PubMed  Google Scholar 

  7. Chatterjee TK, Liu Z, Fisher RA. Human RGS6 gene structure, complex alternative splicing, and role of N terminus and G protein gamma-subunit-like (GGL) domain in subcellular localization of RGS6 splice variants. J Biol Chem. 2003;278(32):30261–71.

    Article  CAS  PubMed  Google Scholar 

  8. Witherow DS, Wang Q, Levay K, Cabrera JL, Chen J, Willars GB, et al. Complexes of the G protein subunit Gbeta 5 with the regulators of G protein signaling RGS7 and RGS9. Characterization in native tissues and in transfected cells. J Biol Chem. 2000;275(32):24872–80.

    Article  CAS  PubMed  Google Scholar 

  9. Snow BE, Betts L, Mangion J, Sondek J, Siderovski DP. Fidelity of G protein beta-subunit association by the G protein gamma-subunit-like domains of RGS6, RGS7, and RGS11. Proc Natl Acad Sci U S A. 1999;96(11):6489–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Posner BA, Gilman AG, Harris BA. Regulators of G protein signaling 6 and 7. Purification of complexes with Gbeta5 and assessment of their effects on G protein-mediated signaling pathways. J Biol Chem. 1999;274(43):31087–93.

    Article  CAS  PubMed  Google Scholar 

  11. Chen CK, Eversole-Cire P, Zhang H, Mancino V, Chen YJ, He W, et al. Instability of GGL domain-containing RGS proteins in mice lacking the G protein beta-subunit Gbeta5. Proc Natl Acad Sci U S A. 2003;100(11):6604–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Porter MY, Xie K, Pozharski E, Koelle MR, Martemyanov KA. A conserved protein interaction interface on the type 5 G protein beta subunit controls proteolytic stability and activity of R7 family regulator of G protein signaling proteins. J Biol Chem. 2010;285(52):41100–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Narayanan V, Sandiford SL, Wang Q, Keren-Raifman T, Levay K, Slepak VZ. Intramolecular interaction between the DEP domain of RGS7 and the Gbeta5 subunit. Biochemistry. 2007;46(23):6859–70.

    Article  CAS  PubMed  Google Scholar 

  14. Cheever ML, Snyder JT, Gershburg S, Siderovski DP, Harden TK, Sondek J. Crystal structure of the multifunctional Gbeta5-RGS9 complex. Nat Struct Mol Biol. 2008;15(2):155–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Drenan RM, Doupnik CA, Jayaraman M, Buchwalter AL, Kaltenbronn KM, Huettner JE, et al. R7BP augments the function of RGS7*Gbeta5 complexes by a plasma membrane-targeting mechanism. J Biol Chem. 2006;281(38):28222–31.

    Article  CAS  PubMed  Google Scholar 

  16. Zhang JH, Barr VA, Mo Y, Rojkova AM, Liu S, Simonds WF. Nuclear localization of G protein beta 5 and regulator of G protein signaling 7 in neurons and brain. J Biol Chem. 2001;276(13):10284–9.

    Article  CAS  PubMed  Google Scholar 

  17. Bouhamdan M, Michelhaugh SK, Calin-Jageman I, Ahern-Djamali S, Bannon MJ. Brain-specific RGS9-2 is localized to the nucleus via its unique proline-rich domain. Biochim Biophys Acta. 2004;1691(2–3):141–50.

    Article  CAS  PubMed  Google Scholar 

  18. Rojkova AM, Woodard GE, Huang TC, Combs CA, Zhang JH, Simonds WF. Ggamma subunit-selective G protein beta 5 mutant defines regulators of G protein signaling protein binding requirement for nuclear localization. J Biol Chem. 2003;278(14):12507–12.

    Article  CAS  PubMed  Google Scholar 

  19. Panicker LM, Zhang JH, Posokhova E, Gastinger MJ, Martemyanov KA, Simonds WF. Nuclear localization of the G protein beta 5/R7-regulator of G protein signaling protein complex is dependent on R7 binding protein. J Neurochem. 2010;113(5):1101–12.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Hooks SB, Waldo GL, Corbitt J, Bodor ET, Krumins AM, Harden TK. RGS6, RGS7, RGS9, and RGS11 stimulate GTPase activity of Gi family G-proteins with differential selectivity and maximal activity. J Biol Chem. 2003;278(12):10087–93.

    Article  CAS  PubMed  Google Scholar 

  21. Stewart A, Maity B, Anderegg SP, Allamargot C, Yang J, Fisher RA. Regulator of G protein signaling 6 is a critical mediator of both reward-related behavioral and pathological responses to alcohol. Proc Natl Acad Sci U S A. 2015;112(7):E786–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Stewart A, Maity B, Wunsch AM, Meng F, Wu Q, Wemmie JA, et al. Regulator of G-protein signaling 6 (RGS6) promotes anxiety and depression by attenuating serotonin-mediated activation of the 5-HT(1A) receptor-adenylyl cyclase axis. FASEB J. 2014;28(4):1735–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Bifsha P, Yang J, Fisher RA, Drouin J. Rgs6 is required for adult maintenance of dopaminergic neurons in the ventral substantia nigra. PLoS Genet. 2014;10(12):e1004863.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Moon SW, Dinov ID, Kim J, Zamanyan A, Hobel S, Thompson PM, et al. Structural neuroimaging genetics interactions in Alzheimer’s disease. J Alzheimers Dis. 2015;48(4):1051–63.

    Article  CAS  PubMed  Google Scholar 

  25. Schizophrenia Working Group of the Psychiatric Genomics Constorium. Biological insights from 108 schizophrenia-associated genetic loci. Nature. 2014;511(7510):421–7.

  26. Chograni M, Alkuraya FS, Maazoul F, Lariani I, Chaabouni-Bouhamed H. RGS6: a novel gene associated with congenital cataract, mental retardation, and microcephaly in a Tunisian family. Invest Ophthalmol Vis Sci. 2015;56(2):1261–6.

    Article  CAS  Google Scholar 

  27. Berman DM, Wang Y, Liu Z, Dong Q, Burke LA, Liotta LA, et al. A functional polymorphism in RGS6 modulates the risk of bladder cancer. Cancer Res. 2004;64(18):6820–6.

    Article  CAS  PubMed  Google Scholar 

  28. Maity B, Stewart A, O’Malley Y, Askeland RW, Sugg SL, Fisher RA. Regulator of G protein signaling 6 is a novel suppressor of breast tumor initiation and progression. Carcinogenesis. 2013;34(8):1747–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Maity B, Yang J, Huang J, Askeland RW, Bera S, Fisher RA. Regulator of G protein signaling 6 (RGS6) induces apoptosis via a mitochondrial-dependent pathway not involving its GTPase-activating protein activity. J Biol Chem. 2011;286(2):1409–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Huang J, Yang J, Maity B, Mayuzumi D, Fisher RA. Regulator of G protein signaling 6 mediates doxorubicin-induced ATM and p53 activation by a reactive oxygen species-dependent mechanism. Cancer Res. 2011;71(20):6310–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Gold SJ, Ni YG, Dohlman HG, Nestler EJ. Regulators of G-protein signaling (RGS) proteins: region-specific expression of nine subtypes in rat brain. J Neurosci. 1997;17(20):8024–37.

    CAS  PubMed  Google Scholar 

  32. Chatterjee TK, Fisher RA. Mild heat and proteotoxic stress promote unique subcellular trafficking and nucleolar accumulation of RGS6 and other RGS proteins. Role of the RGS domain in stress-induced trafficking of RGS proteins. J Biol Chem. 2003;278(32):30272–82.

    Article  CAS  PubMed  Google Scholar 

  33. Maity B, Stewart A, Yang J, Loo L, Sheff D, Shepherd AJ, et al. Regulator of G protein signaling 6 (RGS6) protein ensures coordination of motor movement by modulating GABAB receptor signaling. J Biol Chem. 2012;287(7):4972–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Stewart A, Maity B, Fisher RA. Two for the price of one: G protein-dependent and -independent functions of rgs6 in vivo. Prog Mol Biol Transl Sci. 2015;133:123–51.

    Article  PubMed  Google Scholar 

  35. Brodie MS, Pesold C, Appel SB. Ethanol directly excites dopaminergic ventral tegmental area reward neurons. Alcohol Clin Exp Res. 1999;23(11):1848–52.

    Article  CAS  PubMed  Google Scholar 

  36. Rassnick S, Pulvirenti L, Koob GF. Oral ethanol self-administration in rats is reduced by the administration of dopamine and glutamate receptor antagonists into the nucleus accumbens. Psychopharmacology (Berlin). 1992;109(1–2):92–8.

    Article  CAS  Google Scholar 

  37. Theile JW, Morikawa H, Gonzales RA, Morrisett RA. Ethanol enhances GABAergic transmission onto dopamine neurons in the ventral tegmental area of the rat. Alcohol Clin Exp Res. 2008;32(6):1040–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Xiao C, Shao XM, Olive MF, Griffin 3rd WC, Li KY, Krnjevic K, et al. Ethanol facilitates glutamatergic transmission to dopamine neurons in the ventral tegmental area. Neuropsychopharmacology. 2009;34(2):307–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Diamond I, Gordon AS. Cellular and molecular neuroscience of alcoholism. Physiol Rev. 1997;77(1):1–20.

    CAS  PubMed  Google Scholar 

  40. Sari Y, Johnson VR, Weedman JM. Role of the serotonergic system in alcohol dependence: from animal models to clinics. Prog Mol Biol Transl Sci. 2011;98:401–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Swift R. Medications acting on the dopaminergic system in the treatment of alcoholic patients. Curr Pharm Des. 2010;16(19):2136–40.

    Article  CAS  PubMed  Google Scholar 

  42. Oslin DW, Berrettini WH, O’Brien CP. Targeting treatments for alcohol dependence: the pharmacogenetics of naltrexone. Addict Biol. 2006;11(3–4):397–403.

    Article  CAS  PubMed  Google Scholar 

  43. Addolorato G, Caputo F, Capristo E, Janiri L, Bernardi M, Agabio R, et al. Rapid suppression of alcohol withdrawal syndrome by baclofen. Am J Med. 2002;112(3):226–9.

    Article  PubMed  Google Scholar 

  44. Addolorato G, Leggio L. Safety and efficacy of baclofen in the treatment of alcohol-dependent patients. Curr Pharm Des. 2010;16(19):2113–7.

    Article  CAS  PubMed  Google Scholar 

  45. de Beaurepaire R. Suppression of alcohol dependence using baclofen: a 2-year observational study of 100 patients. Frontiers in Psychiatry. 2012;3:103.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Garzon J, Lopez-Fando A, Sanchez-Blazquez P. The R7 subfamily of RGS proteins assists tachyphylaxis and acute tolerance at mu-opioid receptors. Neuropsychopharmacology. 2003;28(11):1983–90.

    Article  CAS  PubMed  Google Scholar 

  47. Gaspari S, Papachatzaki MM, Koo JW, Carr FB, Tsimpanouli ME, Stergiou E, et al. Nucleus accumbens-specific interventions in RGS9-2 activity modulate responses to morphine. Neuropsychopharmacology. 2014;39(8):1968–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Sutton LP, Ostrovskaya O, Dao M, Xie K, Orlandi C, Smith R, et al. Regulator of G-protein signaling 7 regulates reward behavior by controlling opioid signaling in the striatum. Biol Psychiatry. 2015.

  49. Zachariou V, Georgescu D, Sanchez N, Rahman Z, DiLeone R, Berton O, et al. Essential role for RGS9 in opiate action. Proc Natl Acad Sci U S A. 2003;100(23):13656–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Psifogeorgou K, Terzi D, Papachatzaki MM, Varidaki A, Ferguson D, Gold SJ, et al. A unique role of RGS9-2 in the striatum as a positive or negative regulator of opiate analgesia. J Neurosci. 2011;31(15):5617–24.

    Article  PubMed  CAS  Google Scholar 

  51. Lopez-Fando A, Rodriguez-Munoz M, Sanchez-Blazquez P, Garzon J. Expression of neural RGS-R7 and Gbeta5 proteins in response to acute and chronic morphine. Neuropsychopharmacology. 2005;30(1):99–110.

    Article  CAS  PubMed  Google Scholar 

  52. Pompeiano M, Palacios JM, Mengod G. Distribution and cellular localization of mRNA coding for 5-HT1A receptor in the rat brain: correlation with receptor binding. J Neurosci. 1992;12(2):440–53.

    CAS  PubMed  Google Scholar 

  53. Samuels BA, Mendez-David I, Faye C, David SA, Pierz KA, Gardier AM, et al. Serotonin 1A and serotonin 4 receptors: essential mediators of the neurogenic and behavioral actions of antidepressants. Neuroscientist. 2016;22(1):26–45.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Zhou FC, Patel TD, Swartz D, Xu Y, Kelley MR. Production and characterization of an anti-serotonin 1A receptor antibody which detects functional 5-HT1A binding sites. Brain Res Mol Brain Res. 1999;69(2):186–201.

    Article  CAS  PubMed  Google Scholar 

  55. Santana N, Bortolozzi A, Serrats J, Mengod G, Artigas F. Expression of serotonin1A and serotonin2 A receptors in pyramidal and GABAergic neurons of the rat prefrontal cortex. Cereb Cortex. 2004;14(10):1100–9.

    Article  PubMed  Google Scholar 

  56. Gross C, Zhuang X, Stark K, Ramboz S, Oosting R, Kirby L, et al. Serotonin1A receptor acts during development to establish normal anxiety-like behaviour in the adult. Nature. 2002;416(6879):396–400.

    Article  CAS  PubMed  Google Scholar 

  57. Ramboz S, Oosting R, Amara DA, Kung HF, Blier P, Mendelsohn M, et al. Serotonin receptor 1A knockout: an animal model of anxiety-related disorder. Proc Natl Acad Sci U S A. 1998;95(24):14476–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Parks CL, Robinson PS, Sibille E, Shenk T, Toth M. Increased anxiety of mice lacking the serotonin1A receptor. Proc Natl Acad Sci U S A. 1998;95(18):10734–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Heisler LK, Chu HM, Brennan TJ, Danao JA, Bajwa P, Parsons LH, et al. Elevated anxiety and antidepressant-like responses in serotonin 5-HT1A receptor mutant mice. Proc Natl Acad Sci U S A. 1998;95(25):15049–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Sibille E, Pavlides C, Benke D, Toth M. Genetic inactivation of the serotonin(1A) receptor in mice results in downregulation of major GABA(A) receptor alpha subunits, reduction of GABA(A) receptor binding, and benzodiazepine-resistant anxiety. J Neurosci. 2000;20(8):2758–65.

    CAS  PubMed  Google Scholar 

  61. Talbot JN, Jutkiewicz EM, Graves SM, Clemans CF, Nicol MR, Mortensen RM, et al. RGS inhibition at G(alpha)i2 selectively potentiates 5-HT1A-mediated antidepressant effects. Proc Natl Acad Sci U S A. 2010;107(24):11086–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Andrade R, Huereca D, Lyons JG, Andrade EM, McGregor KM. 5-HT1A receptor-mediated autoinhibition and the control of serotonergic cell firing. ACS Chem Neurosci. 2015;6(7):1110–5.

    Article  CAS  PubMed  Google Scholar 

  63. Martin KF, Phillips I, Hearson M, Prow MR, Heal DJ. Characterization of 8-OH-DPAT-induced hypothermia in mice as a 5-HT1A autoreceptor response and its evaluation as a model to selectively identify antidepressants. Br J Pharmacol. 1992;107(1):15–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Hohoff C, Neumann A, Domschke K, Jacob C, Maier W, Fritze J, et al. Association analysis of Rgs7 variants with panic disorder. J Neural Transm. 2009;116(11):1523–8.

    Article  CAS  PubMed  Google Scholar 

  65. Ghavami A, Hunt RA, Olsen MA, Zhang J, Smith DL, Kalgaonkar S, et al. Differential effects of regulator of G protein signaling (RGS) proteins on serotonin 5-HT1A, 5-HT2A, and dopamine D2 receptor-mediated signaling and adenylyl cyclase activity. Cell Signal. 2004;16(6):711–21.

    Article  CAS  PubMed  Google Scholar 

  66. Jedema HP, Gold SJ, Gonzalez-Burgos G, Sved AF, Tobe BJ, Wensel T, et al. Chronic cold exposure increases RGS7 expression and decreases alpha(2)-autoreceptor-mediated inhibition of noradrenergic locus coeruleus neurons. Eur J Neurosci. 2008;27(9):2433–43.

    Article  PubMed  PubMed Central  Google Scholar 

  67. Terzi D, Gaspari S, Manouras L, Descalzi G, Mitsi V, Zachariou V. RGS9-2 modulates sensory and mood related symptoms of neuropathic pain. Neurobiol Learn Mem. 2014;115:43–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Fahn S. The history of dopamine and levodopa in the treatment of Parkinson’s disease. Movement Disord. 2008;23 Suppl 3:S497–508.

    Article  PubMed  Google Scholar 

  69. Meissner WG, Frasier M, Gasser T, Goetz CG, Lozano A, Piccini P, et al. Priorities in Parkinson’s disease research. Nat Rev Drug Discov. 2011;10(5):377–93.

    Article  CAS  PubMed  Google Scholar 

  70. Shulman JM, De Jager PL, Feany MB. Parkinson’s disease: genetics and pathogenesis. Annu Rev Pathol. 2011;6:193–222.

    Article  CAS  PubMed  Google Scholar 

  71. Nussbaum RL, Ellis CE. Alzheimer’s disease and Parkinson’s disease. N Engl J Med. 2003;348(14):1356–64.

    Article  CAS  PubMed  Google Scholar 

  72. Dawson TM, Ko HS, Dawson VL. Genetic animal models of Parkinson’s disease. Neuron. 2010;66(5):646–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Hwang DY, Ardayfio P, Kang UJ, Semina EV, Kim KS. Selective loss of dopaminergic neurons in the substantia nigra of Pitx3-deficient aphakia mice. Brain Res Mol Brain Res. 2003;114(2):123–31.

    Article  CAS  PubMed  Google Scholar 

  74. Nunes I, Tovmasian LT, Silva RM, Burke RE, Goff SP. Pitx3 is required for development of substantia nigra dopaminergic neurons. Proc Natl Acad Sci U S A. 2003;100(7):4245–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. van den Munckhof P, Luk KC, Ste-Marie L, Montgomery J, Blanchet PJ, Sadikot AF, et al. Pitx3 is required for motor activity and for survival of a subset of midbrain dopaminergic neurons. Development. 2003;130(11):2535–42.

    Article  PubMed  CAS  Google Scholar 

  76. van den Munckhof P, Gilbert F, Chamberland M, Levesque D, Drouin J. Striatal neuroadaptation and rescue of locomotor deficit by L-dopa in aphakia mice, a model of Parkinson’s disease. J Neurochem. 2006;96(1):160–70.

    Article  PubMed  CAS  Google Scholar 

  77. Hwang DY, Fleming SM, Ardayfio P, Moran-Gates T, Kim H, Tarazi FI, et al. 3,4-dihydroxyphenylalanine reverses the motor deficits in Pitx3-deficient aphakia mice: behavioral characterization of a novel genetic model of Parkinson’s disease. J Neurosci. 2005;25(8):2132–7.

    Article  CAS  PubMed  Google Scholar 

  78. Fuchs J, Mueller JC, Lichtner P, Schulte C, Munz M, Berg D, et al. The transcription factor PITX3 is associated with sporadic Parkinson’s disease. Neurobiol Aging. 2009;30(5):731–8.

    Article  CAS  PubMed  Google Scholar 

  79. Westerlund M, Hoffer B, Olson L. Parkinson’s disease: exit toxins, enter genetics. Prog Neurobiol. 2010;90(2):146–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Ford CP. The role of D2-autoreceptors in regulating dopamine neuron activity and transmission. Neuroscience. 2014;282C:13–22.

    Article  CAS  PubMed  Google Scholar 

  81. Holtje M, von Jagow B, Pahner I, Lautenschlager M, Hortnagl H, Nurnberg B, et al. The neuronal monoamine transporter VMAT2 is regulated by the trimeric GTPase Go(2). J Neurosci. 2000;20(6):2131–41.

    CAS  PubMed  Google Scholar 

  82. Gonzalez-Hernandez T, Cruz-Muros I, Afonso-Oramas D, Salas-Hernandez J, Castro-Hernandez J. Vulnerability of mesostriatal dopaminergic neurons in Parkinson’s disease. Front Neuroanat. 2010;4:140.

    Article  PubMed  PubMed Central  Google Scholar 

  83. Afonso-Oramas D, Cruz-Muros I, de la Alvarez Rosa D, Abreu P, Giraldez T, Castro-Hernandez J, et al. Dopamine transporter glycosylation correlates with the vulnerability of midbrain dopaminergic cells in Parkinson’s disease. Neurobiol Dis. 2009;36(3):494–508.

    Article  CAS  PubMed  Google Scholar 

  84. Tekumalla PK, Calon F, Rahman Z, Birdi S, Rajput AH, Hornykiewicz O, et al. Elevated levels of DeltaFosB and RGS9 in striatum in Parkinson’s disease. Biol Psychiatry. 2001;50(10):813–6.

    Article  CAS  PubMed  Google Scholar 

  85. Gold SJ, Hoang CV, Potts BW, Porras G, Pioli E, Kim KW, et al. RGS9-2 negatively modulates L-3,4-dihydroxyphenylalanine-induced dyskinesia in experimental Parkinson’s disease. J Neurosci. 2007;27(52):14338–48.

    Article  CAS  PubMed  Google Scholar 

  86. Bergen SE, O’Dushlaine CT, Ripke S, Lee PH, Ruderfer DM, Akterin S, et al. Genome-wide association study in a Swedish population yields support for greater CNV and MHC involvement in schizophrenia compared with bipolar disorder. Mol Psychiatry. 2012;17(9):880–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Seeman P, Ko F, Jack E, Greenstein R, Dean B. Consistent with dopamine supersensitivity, RGS9 expression is diminished in the amphetamine-treated animal model of schizophrenia and in postmortem schizophrenia brain. Synapse. 2007;61(5):303–9.

    Article  CAS  PubMed  Google Scholar 

  88. Muma NA, Singh RK, Vercillo MS, D’Souza DN, Zemaitaitis B, Garcia F, et al. Chronic olanzapine activates the Stat3 signal transduction pathway and alters expression of components of the 5-HT2A receptor signaling system in rat frontal cortex. Neuropharmacology. 2007;53(4):552–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Singh RK, Dai Y, Staudinger JL, Muma NA. Activation of the JAK-STAT pathway is necessary for desensitization of 5-HT2A receptor-stimulated phospholipase C signalling by olanzapine, clozapine and MDL 100907. Int J Neuropsychopharmacol. 2009;12(5):651–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Singh RK, Shi J, Zemaitaitis BW, Muma NA. Olanzapine increases RGS7 protein expression via stimulation of the Janus tyrosine kinase-signal transducer and activator of transcription signaling cascade. J Pharmacol Exp Ther. 2007;322(1):133–40.

    Article  CAS  PubMed  Google Scholar 

  91. Chertkow Y, Weinreb O, Youdim MB, Silver H. Gene expression changes in peripheral mononuclear cells from schizophrenic patients treated with a combination of antipsychotic with fluvoxamine. Prog Neuropsychopharmacol Biol Psychiatry. 2007;31(7):1356–62.

    Article  CAS  PubMed  Google Scholar 

  92. Rahman Z, Schwarz J, Gold SJ, Zachariou V, Wein MN, Choi KH, et al. RGS9 modulates dopamine signaling in the basal ganglia. Neuron. 2003;38(6):941–52.

    Article  CAS  PubMed  Google Scholar 

  93. Walker PD, Jarosz PA, Bouhamdan M, MacKenzie RG. Effects of gender on locomotor sensitivity to amphetamine, body weight, and fat mass in regulator of G protein signaling 9 (RGS9) knockout mice. Physiol Behav. 2015;138:305–12.

    Article  CAS  PubMed  Google Scholar 

  94. Chen FS, Shim H, Morhardt D, Dallman R, Krahn E, McWhinney L, et al. Functional redundancy of R7 RGS proteins in ON-bipolar cell dendrites. Invest Ophthalmol Vis Sci. 2010;51(2):686–93.

    Article  PubMed  PubMed Central  Google Scholar 

  95. Chen CK, Burns ME, He W, Wensel TG, Baylor DA, Simon MI. Slowed recovery of rod photoresponse in mice lacking the GTPase accelerating protein RGS9-1. Nature. 2000;403(6769):557–60.

    Article  CAS  PubMed  Google Scholar 

  96. Krispel CM, Chen CK, Simon MI, Burns ME. Prolonged photoresponses and defective adaptation in rods of Gbeta5−/− mice. J Neurosci. 2003;23(18):6965–71.

    CAS  PubMed  Google Scholar 

  97. Cao Y, Pahlberg J, Sarria I, Kamasawa N, Sampath AP, Martemyanov KA. Regulators of G protein signaling RGS7 and RGS11 determine the onset of the light response in ON bipolar neurons. Proc Natl Acad Sci U S A. 2012;109(20):7905–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Dorsam RT, Gutkind JS. G-protein-coupled receptors and cancer. Nat Rev Cancer. 2007;7(2):79–94.

    Article  CAS  PubMed  Google Scholar 

  99. Dai J, Gu J, Lu C, Lin J, Stewart D, Chang D, et al. Genetic variations in the regulator of G-protein signaling genes are associated with survival in late-stage non-small cell lung cancer. PLoS One. 2011;6(6):e21120.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Gu J, Wu X, Dong Q, Romeo MJ, Lin X, Gutkind JS, et al. A nonsynonymous single-nucleotide polymorphism in the PDZ-Rho guanine nucleotide exchange factor (Ser1416Gly) modulates the risk of lung cancer in Mexican Americans. Cancer. 2006;106(12):2716–24.

    Article  CAS  PubMed  Google Scholar 

  101. Jiang N, Xue R, Bu F, Tong X, Qiang J, Liu R. Decreased RGS6 expression is associated with poor prognosis in pancreatic cancer patients. Int J Clin Exp Pathol. 2014;7(7):4120–7.

    PubMed  PubMed Central  Google Scholar 

  102. Hurst JH, Mendpara N, Hooks SB. Regulator of G-protein signalling expression and function in ovarian cancer cell lines. Cell Mol Biol Lett. 2009;14(1):153–74.

    Article  CAS  PubMed  Google Scholar 

  103. Martinez-Cardus A, Martinez-Balibrea E, Bandres E, Malumbres R, Gines A, Manzano JL, et al. Pharmacogenomic approach for the identification of novel determinants of acquired resistance to oxaliplatin in colorectal cancer. Mol Cancer Ther. 2009;8(1):194–202.

    Article  CAS  PubMed  Google Scholar 

  104. Doyle DM, Miller KD. Development of new targeted therapies for breast cancer. Cancer Treat Res. 2008;141:119–34.

    Article  PubMed  Google Scholar 

  105. Jager A, Verweij J, Sleijfer S. Chemotherapy: adjuvant chemotherapy in older patients with breast cancer. Nat Rev Clin Oncol. 2009;6(10):563–5.

    Article  CAS  PubMed  Google Scholar 

  106. Tewey KM, Rowe TC, Yang L, Halligan BD, Liu LF. Adriamycin-induced DNA damage mediated by mammalian DNA topoisomerase II. Science. 1984;226(4673):466–8.

    Article  CAS  PubMed  Google Scholar 

  107. Lown JW, Sim SK, Majumdar KC, Chang RY. Strand scission of DNA by bound adriamycin and daunorubicin in the presence of reducing agents. Biochem Biophys Res Commun. 1977;76(3):705–10.

    Article  CAS  PubMed  Google Scholar 

  108. Kurz EU, Douglas P, Lees-Miller SP. Doxorubicin activates ATM-dependent phosphorylation of multiple downstream targets in part through the generation of reactive oxygen species. J Biol Chem. 2004;279(51):53272–81.

    Article  CAS  PubMed  Google Scholar 

  109. Guo Z, Deshpande R, Paull TT. ATM activation in the presence of oxidative stress. Cell Cycle. 2010;9(24):4805–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Huang J, Stewart A, Maity B, Hagen J, Fagan RL, Yang J, et al. RGS6 suppresses Ras-induced cellular transformation by facilitating Tip60-mediated Dnmt1 degradation and promoting apoptosis. Oncogene. 2014;33(27):3604–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Patra SK, Patra A, Zhao H, Dahiya R. DNA methyltransferase and demethylase in human prostate cancer. Mol Carcinog. 2002;33(3):163–71.

  112. Li LC, Okino ST, Dahiya R. DNA methylation in prostate cancer. Biochim Biophys Acta. 2004;1704(2):87–102.

  113. Lopez-Serra L, Ballestar E, Fraga MF, Alaminos M, Setien F, Esteller M. A profile of methyl-CpG binding domain protein occupancy of hypermethylated promoter CpG islands of tumor suppressor genes in human cancer. Cancer Res. 2006;66(17):8342–6.

  114. Esteller M. Aberrant DNA methylation as a cancer-inducing mechanism. Annu Rev Pharmacol Toxicol. 2005;45:629–56.

  115. el-Deiry WS, Nelkin BD, Celano P, Yen RW, Falco JP, Hamilton SR, et al. High expression of the DNA methyltransferase gene characterizes human neoplastic cells and progression stages of colon cancer. Proc Natl Acad Sci U S A. 1991;88(8):3470–4.

  116. He S, Wang F, Yang L, Guo C, Wan R, Ke A, et al. Expression of DNMT1 and DNMT3a are regulated by GLI1 in human pancreatic cancer. PLoS One. 2011;6(11):e27684.

  117. Nakagawa T, Kanai Y, Saito Y, Kitamura T, Kakizoe T, Hirohashi S. Increased DNA methyltransferase 1 protein expression in human transitional cell carcinoma of the bladder. J Urol. 2003;170(6 Pt 1):2463–6.

  118. Saito Y, Kanai Y, Nakagawa T, Sakamoto M, Saito H, Ishii H, et al. Increased protein expression of DNA methyltransferase (DNMT) 1 is significantly correlated with the malignant potential and poor prognosis of human hepatocellular carcinomas. Int J Cancer. 2003;105(4):527–32.

  119. Etoh T, Kanai Y, Ushijima S, Nakagawa T, Nakanishi Y, Sasako M, et al. Increased DNA methyltransferase 1 (DNMT1) protein expression correlates significantly with poorer tumor differentiation and frequent DNA hypermethylation of multiple CpG islands in gastric cancers. Am J Pathol. 2004;164(2):689–99.

  120. Peng DF, Kanai Y, Sawada M, Ushijima S, Hiraoka N, Kosuge T, et al. Increased DNA methyltransferase 1 (DNMT1) protein expression in precancerous conditions and ductal carcinomas of the pancreas. Cancer Sci. 2005;96(7):403–8.

  121. Zhu YM, Huang Q, Lin J, Hu Y, Chen J, Lai MD. Expression of human DNA methyltransferase 1 in colorectal cancer tissues and their corresponding distant normal tissues. Int J Colorectal Dis. 2007;22(6):661–6.

  122. Ordway JM, Williams K, Curran T. Transcription repression in oncogenic transformation: common targets of epigenetic repression in cells transformed by Fos, Ras or Dnmt1. Oncogene. 2004;23(21):3737–48.

  123. Patra SK. Ras regulation of DNA-methylation and cancer. Exp Cell Res. 2008;314(6):1193–201.

  124. Patra SK, Szyf M. DNA methylation-mediated nucleosome dynamics and oncogenic Ras signaling: insights from FAS, FAS ligand and RASSF1A. The FEBS journal. 2008;275(21):5217–35.

  125. Bestor TH. The DNA, methyltransferases of mammals. Hum Mol Genet. 2000;9(16):2395–402.

    Article  CAS  PubMed  Google Scholar 

  126. Leonhardt H, Cardoso MC. DNA methylation, nuclear structure, gene expression and cancer. J Cell Biochem Suppl. 2000;79 Suppl 35:78–83.

    Article  Google Scholar 

  127. Liu Z, Fisher RA. RGS6 interacts with DMAP1 and DNMT1 and inhibits DMAP1 transcriptional repressor activity. J Biol Chem. 2004;279(14):14120–8.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

The work presented in this review article was largely supported by a grant from the National Cancer Institute, CA161882, and by a grant from the American Heart Association, 14GRNT20460208. We thank our collaborators as well as current and past Fisher laboratory members who contributed to the studies described here.

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Correspondence to Rory A. Fisher.

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Guest Editor: Shelley Hooks

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Ahlers, K.E., Chakravarti, B. & Fisher, R.A. RGS6 as a Novel Therapeutic Target in CNS Diseases and Cancer. AAPS J 18, 560–572 (2016). https://doi.org/10.1208/s12248-016-9899-9

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