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PMID: 10793158 Published · ppublish English Journal Article

Involvement of a small GTP-binding protein (G protein) regulator, small G protein GDP dissociation stimulator, in antiapoptotic cell survival signaling.

Molecular biology of the cell ·Vol. 11 ·No. 5 ·2000-05-00 ·Pages 1875-86

Takakura A, Miyoshi J, Ishizaki H, Tanaka M, Togawa A, Nishizawa Y, Yoshida H, Nishikawa Si, Takai Y

Abstract

Small GTP-binding protein GDP dissociation stimulator (Smg GDS) regulates GDP/GTP exchange reaction of Ki-Ras and the Rho and Rap1 family members and inhibits their binding to membranes. In fibroblasts, Smg GDS shows mitogenic and transforming activities in cooperation with Ki-Ras. However, the physiological function of Smg GDS remains unknown. Here we show that mice lacking Smg GDS died of heart failure shortly after birth, not resulting from developmental heart defects but from enhanced apoptosis of cardiomyocytes triggered by cardiovascular overload. Furthermore, neonatal thymocytes and developing neuronal cells underwent apoptotic cell death. Smg GDS-/- thymocytes were susceptible to apoptotic inducers, such as etoposide and UV irradiation. Smg GDS-/- thymocytes were protected from etoposide-induced cell death by ex vivo transduction of the Smg GDS cDNA. These phenotypes partly coincide with those observed in Ki-Ras-deficient mice, suggesting that Smg GDS is involved in antiapoptotic cell survival signaling through Ki-Ras.

MeSH Terms
Animals Animals, Newborn Apoptosis/drug effects,physiology,radiation effects Cell Survival/physiology Cells, Cultured Etoposide/pharmacology Female GTP-Binding Proteins/genetics,metabolism Genes, ras Heart Defects, Congenital/pathology Mice Mice, Inbred C57BL Mice, Transgenic Myocardium/pathology Neurons/pathology Signal Transduction Survival Rate Thymus Gland/drug effects,growth & development,pathology,radiation effects Ultraviolet Rays
Chemicals
Etoposide GTP-Binding Proteins
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Takakura A
Takai Biotimer Project, Exploratory Research in Advanced Technology, Japan Science and Technology Corporation, c/o JCR Pharmaceuticals, Kobe 651-2241, Japan.
Miyoshi J
Ishizaki H
Tanaka M
Togawa A
Nishizawa Y
Yoshida H
Nishikawa S i
Takai Y
References (57)
57 references, click to expand
  1. The Son of sevenless gene product: a putative activator of Ras.
    Science. 1992 Jan 31;255(5044):603-6 PMID: 1736363
  2. Loss of a gp130 cardiac muscle cell survival pathway is a critical event in the onset of heart failure during biomechanical stress.
    Cell. 1999 Apr 16;97(2):189-98 PMID: 10219240
  3. Microinjection of smg/rap1/Krev-1 p21 into Swiss 3T3 cells induces DNA synthesis and morphological changes.
    Mol Cell Biol. 1992 Aug;12(8):3407-14 PMID: 1321333
  4. Functional interactions of stimulatory and inhibitory GDP/GTP exchange proteins and their common substrate small GTP-binding protein.
    J Biol Chem. 1992 Jul 25;267(21):14611-5 PMID: 1634508
  5. The functional domain of the stimulatory GDP/GTP exchange protein (smg GDS) which interacts with the C-terminal geranylgeranylated region of rap1/Krev-1/smg p21.
    Oncogene. 1992 Sep;7(9):1699-704 PMID: 1501882
  6. Post-translational processing of rac p21s is important both for their interaction with the GDP/GTP exchange proteins and for their activation of NADPH oxidase.
    J Biol Chem. 1992 Dec 25;267(36):25709-13 PMID: 1464587
  7. Translocation of Ki-ras p21 between membrane and cytoplasm by smg GDS.
    Biochem Biophys Res Commun. 1993 Feb 15;190(3):832-41 PMID: 8439333
  8. p53 is required for radiation-induced apoptosis in mouse thymocytes.
    Nature. 1993 Apr 29;362(6423):847-9 PMID: 8479522
  9. Association of Sos Ras exchange protein with Grb2 is implicated in tyrosine kinase signal transduction and transformation.
    Nature. 1993 May 6;363(6424):45-51 PMID: 8479536
  10. Epidermal growth factor regulates p21ras through the formation of a complex of receptor, Grb2 adapter protein, and Sos nucleotide exchange factor.
    Cell. 1993 May 7;73(3):611-20 PMID: 8490966
  11. Mammalian Ras interacts directly with the serine/threonine kinase Raf.
    Cell. 1993 Jul 16;74(1):205-14 PMID: 8334704
  12. In vitro growth characteristics of embryo fibroblasts isolated from p53-deficient mice.
    Oncogene. 1993 Sep;8(9):2457-67 PMID: 8103211
  13. p53-dependent apoptosis modulates the cytotoxicity of anticancer agents.
    Cell. 1993 Sep 24;74(6):957-67 PMID: 8402885
  14. The catalytic domain of the mouse sos1 gene product activates Ras proteins in vivo and in vitro.
    Oncogene. 1993 Nov;8(11):3081-4 PMID: 8414509
  15. Comparison of kinetic properties between two mammalian ras p21 GDP/GTP exchange proteins, ras guanine nucleotide-releasing factor and smg GDP dissociation stimulation.
    J Biol Chem. 1993 Dec 5;268(34):25542-6 PMID: 8244990
  16. The Dbl oncogene product as a GDP/GTP exchange protein for the Rho family: its properties in comparison with those of Smg GDS.
    Biochem Biophys Res Commun. 1994 Jan 28;198(2):811-7 PMID: 8297393
  17. Regulators of small GTPases.
    Ciba Found Symp. 1993;176:128-38; discussion 138-46 PMID: 8299416
  18. Different functions of Smg GDP dissociation stimulator and mammalian counterpart of yeast Cdc25.
    J Biol Chem. 1994 May 27;269(21):15085-91 PMID: 8195145
  19. The murine N-ras gene is not essential for growth and development.
    Proc Natl Acad Sci U S A. 1995 Feb 28;92(5):1709-13 PMID: 7878045
  20. Myogenic and morphogenetic defects in the heart tubes of murine embryos lacking the homeo box gene Nkx2-5.
    Genes Dev. 1995 Jul 1;9(13):1654-66 PMID: 7628699
  21. Mice lacking p21CIP1/WAF1 undergo normal development, but are defective in G1 checkpoint control.
    Cell. 1995 Aug 25;82(4):675-84 PMID: 7664346
  22. Identification of Rap1 as a target for the Crk SH3 domain-binding guanine nucleotide-releasing factor C3G.
    Mol Cell Biol. 1995 Dec;15(12):6746-53 PMID: 8524240
  23. Suppression of c-Myc-induced apoptosis by Ras signalling through PI(3)K and PKB.
    Nature. 1997 Feb 6;385(6616):544-8 PMID: 9020362
  24. The PI 3-kinase/Akt signaling pathway delivers an anti-apoptotic signal.
    Genes Dev. 1997 Mar 15;11(6):701-13 PMID: 9087425
  25. DFF, a heterodimeric protein that functions downstream of caspase-3 to trigger DNA fragmentation during apoptosis.
    Cell. 1997 Apr 18;89(2):175-84 PMID: 9108473
  26. Short- and long-term effects of low-dose prenatal X-irradiation in mouse cerebral cortex, with special reference to neuronal migration.
    Acta Neuropathol. 1997 May;93(5):443-9 PMID: 9144582
  27. The GTPase Rho has a critical regulatory role in thymus development.
    EMBO J. 1997 May 1;16(9):2397-407 PMID: 9171353
  28. K-ras is essential for the development of the mouse embryo.
    Oncogene. 1997 Sep 4;15(10):1151-9 PMID: 9294608
  29. K-ras is an essential gene in the mouse with partial functional overlap with N-ras.
    Genes Dev. 1997 Oct 1;11(19):2468-81 PMID: 9334313
  30. Tumor suppression at the mouse INK4a locus mediated by the alternative reading frame product p19ARF.
    Cell. 1997 Nov 28;91(5):649-59 PMID: 9393858
  31. A caspase-activated DNase that degrades DNA during apoptosis, and its inhibitor ICAD.
    Nature. 1998 Jan 1;391(6662):43-50 PMID: 9422506
  32. Akt, a target of phosphatidylinositol 3-kinase, inhibits apoptosis in a differentiating neuronal cell line.
    Mol Cell Biol. 1998 Apr;18(4):2143-52 PMID: 9528786
  33. Identification of darlin, a Dictyostelium protein with Armadillo-like repeats that binds to small GTPases and is important for the proper aggregation of developing cells.
    Mol Biol Cell. 1998 Nov;9(11):3095-106 PMID: 9802899
  34. Dying like flies.
    Cell. 1998 Oct 30;95(3):295-8 PMID: 9814699
  35. Ras promotes cell survival in Drosophila by downregulating hid expression.
    Cell. 1998 Oct 30;95(3):319-29 PMID: 9814703
  36. The Drosophila gene hid is a direct molecular target of Ras-dependent survival signaling.
    Cell. 1998 Oct 30;95(3):331-41 PMID: 9814704
  37. Activation of the Ras/mitogen-activated protein kinase pathway by kinase-defective epidermal growth factor receptors results in cell survival but not proliferation.
    Mol Cell Biol. 1998 Dec;18(12):7192-204 PMID: 9819406
  38. Epac is a Rap1 guanine-nucleotide-exchange factor directly activated by cyclic AMP.
    Nature. 1998 Dec 3;396(6710):474-7 PMID: 9853756
  39. A family of cAMP-binding proteins that directly activate Rap1.
    Science. 1998 Dec 18;282(5397):2275-9 PMID: 9856955
  40. Mechanisms and control of programmed cell death in invertebrates.
    Oncogene. 1998 Dec 24;17(25):3215-23 PMID: 9916984
  41. A balance of signaling by Rho family small GTPases RhoA, Rac1 and Cdc42 coordinates cytoskeletal morphology but not cell survival.
    Oncogene. 1999 Jan 7;18(1):47-57 PMID: 9926919
  42. Anti-apoptotic function of Rac in hematopoietic cells.
    Oncogene. 1999 Jan 14;18(2):407-15 PMID: 9927197
  43. Homologous activators of ras in fission and budding yeast.
    Nature. 1990 Mar 22;344(6264):355-7 PMID: 2107403
  44. Enhancement of the GDP-GTP exchange of RAS proteins by the carboxyl-terminal domain of SCD25.
    Science. 1990 May 18;248(4957):866-8 PMID: 2188363
  45. The cellular functions of small GTP-binding proteins.
    Science. 1990 Aug 10;249(4969):635-40 PMID: 2116664
  46. Purification and characterization from bovine brain cytosol of proteins that regulate the GDP/GTP exchange reaction of smg p21s, ras p21-like GTP-binding proteins.
    J Biol Chem. 1990 Sep 25;265(27):16626-34 PMID: 2118909
  47. The GTPase superfamily: a conserved switch for diverse cell functions.
    Nature. 1990 Nov 8;348(6297):125-32 PMID: 2122258
  48. The GTPase superfamily: conserved structure and molecular mechanism.
    Nature. 1991 Jan 10;349(6305):117-27 PMID: 1898771
  49. The CDC25 protein of Saccharomyces cerevisiae promotes exchange of guanine nucleotides bound to ras.
    Mol Cell Biol. 1991 May;11(5):2641-6 PMID: 2017169
  50. Molecular cloning of the cDNA for stimulatory GDP/GTP exchange protein for smg p21s (ras p21-like small GTP-binding proteins) and characterization of stimulatory GDP/GTP exchange protein.
    Mol Cell Biol. 1991 May;11(5):2873-80 PMID: 1901951
  51. A stimulatory GDP/GTP exchange protein for smg p21 is active on the post-translationally processed form of c-Ki-ras p21 and rhoA p21.
    Proc Natl Acad Sci U S A. 1991 Aug 1;88(15):6442-6 PMID: 1907371
  52. Ras1 and a putative guanine nucleotide exchange factor perform crucial steps in signaling by the sevenless protein tyrosine kinase.
    Cell. 1991 Nov 15;67(4):701-16 PMID: 1934068
  53. A homolog of the armadillo protein in Drosophila (plakoglobin) associated with E-cadherin.
    Science. 1991 Nov 29;254(5036):1359-61 PMID: 1962194
  54. Transforming and c-fos promoter/enhancer-stimulating activities of a stimulatory GDP/GTP exchange protein for small GTP-binding proteins.
    J Biol Chem. 1992 Jan 15;267(2):926-30 PMID: 1730682
  55. Progressive impairment of kidneys and reproductive organs in mice lacking Rho GDIalpha.
    Oncogene. 1999 Sep 23;18(39):5373-80 PMID: 10498891
  56. Both stimulatory and inhibitory GDP/GTP exchange proteins, smg GDS and rho GDI, are active on multiple small GTP-binding proteins.
    Biochem Biophys Res Commun. 1992 Jan 31;182(2):921-30 PMID: 1734890
  57. Small GTP-binding proteins.
    Int Rev Cytol. 1992;133:187-230 PMID: 1577587
Article Info
Journal
Molecular biology of the cell
Abbr.
Mol Biol Cell
ISSN
1059-1524
DOI
10.1091/mbc.11.5.1875
Published
2000-05-00
Pages
1875-86
Language
English
Region
United States
NLM ID
9201390
PMCID
PMC14890
Subset
IM
External Links
PubMed source DOI: 10.1091/mbc.11.5.1875 PMC Full Text View journal details
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