Unregulated actin polymerization by WASp causes defects of mitosis and cytokinesis in X-linked neutropenia

被引:128
作者
Moulding, Dale A.
Blundell, Michael P.
Spiller, David G.
White, Michael R. H.
Cory, Giles O.
Calle, Yolanda
Kempski, Helena
Sinclair, Jo
Ancliff, Phil J.
Kinnon, Christine
Jones, Gareth E.
Thrasher, Adrian J. [1 ]
机构
[1] UCL, Inst Child Hlth, Wolfson Ctr Gene Therapy Chilhood Dis, London WC1N 1EH, England
[2] UCL, Inst Child Hlth, Mol Haematol Unit, London WC1N 1EH, England
[3] Ctr Cell Imaging, Sch Biol Sci, Biosci Res Bldg, Liverpool L69 7ZB, Merseyside, England
[4] Univ Bristol, Sch Med Sci, Dept Biochem, Bristol BS8 1TD, Avon, England
[5] Kings Coll London, Randall Div Cell & Mol Biophys, London SE1 1UL, England
[6] Great Ormond St Hosp Sick Children, Dept Haematol, London WC1N 3JH, England
[7] Great Ormond St Hosp Sick Children, Dept Immunol, London WC1N 3JH, England
基金
英国医学研究理事会; 英国生物技术与生命科学研究理事会; 英国惠康基金;
关键词
D O I
10.1084/jem.20062324
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Specific mutations in the human gene encoding the Wiskott-Aldrich syndrome protein ( WASp) that compromise normal auto-inhibition of WASp result in unregulated activation of the actin-related protein 2/ 3 complex and increased actin polymerizing activity. These activating mutations are associated with an X-linked form of neutropenia with an intrinsic failure of myelopoiesis and an increase in the incidence of cytogenetic abnormalities. To study the underlying mechanisms, active mutant WASp(I294T) was expressed by gene transfer. This caused enhanced and delocalized actin polymerization throughout the cell, decreased proliferation, and increased apoptosis. Cells became binucleated, suggesting a failure of cytokinesis, and micronuclei were formed, indicative of genomic instability. Live cell imaging demonstrated a delay in mitosis from prometaphase to anaphase and confirmed that multinucleation was a result of aborted cytokinesis. During mitosis, filamentous actin was abnormally localized around the spindle and chromosomes throughout their alignment and separation, and it accumulated within the cleavage furrow around the spindle midzone. These findings reveal a novel mechanism for inhibition of myelopoiesis through defective mitosis and cytokinesis due to hyperactivation and mislocalization of actin polymerization.
引用
收藏
页码:2213 / 2224
页数:12
相关论文
共 48 条
  • [1] Two novel activating mutations in the Wiskott-Aldrich syndrome protein result in congenital neutropenia
    Ancliff, Phil J.
    Blundell, Michael P.
    Cory, Giles O.
    Calle, Yolanda
    Worth, Austen
    Kempski, Helena
    Burns, Siobhan
    Jones, Gareth E.
    Sinclair, Jo
    Kinnon, Christine
    Hann, Ian M.
    Gale, Rosemary E.
    Linch, David C.
    Thrasher, Adrian J.
    [J]. BLOOD, 2006, 108 (07) : 2182 - 2189
  • [2] Congenital neutropenia
    Ancliff, PJ
    [J]. BLOOD REVIEWS, 2003, 17 (04) : 209 - 216
  • [3] Tetraploid state induces p53-dependent arrest of nontransformed mammalian cells in G1
    Andreassen, PR
    Lohez, OD
    Lacroix, FB
    Margolis, RL
    [J]. MOLECULAR BIOLOGY OF THE CELL, 2001, 12 (05) : 1315 - 1328
  • [4] Effects of jasplakinolide on the kinetics of actin polymerization -: An explanation for certain in vivo observations
    Bubb, MR
    Spector, I
    Beyer, BB
    Fosen, KM
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 2000, 275 (07) : 5163 - 5170
  • [5] BUBB MR, 1994, J BIOL CHEM, V269, P14869
  • [6] Mechanisms of WASp-mediated hematologic and immunologic disease
    Burns, S
    Cory, GO
    Vainchenker, W
    Thrasher, AJ
    [J]. BLOOD, 2004, 104 (12) : 3454 - 3462
  • [7] Apoptosis regulation in tetraploid cancer cells
    Castedo, Maria
    Coquelle, Arnaud
    Vivet, Sonia
    Vitale, Ilio
    Kauffmann, Audrey
    Dessen, Philippe
    Pequignot, Marie O.
    Casares, Noelia
    Valent, Alexandre
    Mouhamad, Shahul
    Schmitt, Elise
    Modjtahedi, Nazanine
    Vainchenker, William
    Zitvogel, Laurence
    Lazar, Vladimir
    Garrido, Carmen
    Kroemer, Guido
    [J]. EMBO JOURNAL, 2006, 25 (11) : 2584 - 2595
  • [8] Phosphorylation of tyrosine enhances the ability of WASp to stimulate actin polymerization and filopodium formation
    Cory, GOC
    Garg, R
    Cramer, R
    Ridley, AJ
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (47) : 45115 - 45121
  • [9] High-level transduction and gene expression in hematopoietic repopulating cells using a human imunodeficiency virus type 1-based lentiviral vector containing an internal spleen focus forming virus promoter
    Demaison, C
    Parsley, K
    Brouns, G
    Scherr, M
    Battmer, K
    Kinnon, C
    Grez, M
    Thrasher, AJ
    [J]. HUMAN GENE THERAPY, 2002, 13 (07) : 803 - 813
  • [10] ISOLATION OF A NOVEL GENE MUTATED IN WISKOTT-ALDRICH SYNDROME
    DERRY, JMJ
    OCHS, HD
    FRANCKE, U
    [J]. CELL, 1994, 78 (04) : 635 - 644