C-Myc activation by Theileria parasites promotes survival of infected B-lymphocytes

被引:69
作者
Dessauge, G
Hilaly, S
Baumgartner, M
Blumen, B
Werling, D
Langsley, G
机构
[1] Inst Pasteur, Dept Parasitol, CNRS URA CNRS 2581, Lab Signalisat Immunoparasitaire, F-75724 Paris 15, France
[2] Univ Calif San Francisco, Dept Stomatol, San Francisco, CA 94143 USA
[3] Royal Vet Coll, N Mymms AL9 7TA, Herts, England
关键词
apoptosis; c-Myc; STAT3; Theileria; transformation;
D O I
10.1038/sj.onc.1208314
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Theileria parasites infect and transform bovine lymphocytes, but host cell immortalization is reversible, as upon parasite death the lymphocytes rapidly die of apoptosis. Infection leads to a marked augmentation in the levels of lymphocyte c-Myc, and the parasite achieves this by inducing increased c-myc transcription and by prolonging the half-life of the transcription factor. Reduction in c-Myc turnover can be ascribed to CK2-mediated phosphorylation of the transcription factor. A parasite-dependent GM-CSF autocrine loop activates a JAK2/ STAT3 signalling pathway that contributes to heightened c-myc transcription, and inhibition of the pathway leads to caspase 9 activation and apoptosis that can be directly ascribed to a reduction in c-Myc. An antiapoptotic role for c-Myc was clearly demonstrated by specific inhibition of c-myc expression with antisense oligonucleotides, and this correlates with loss of the antiapoptotic protein Mcl-1, and, consistently, ectopic expression of c-Myc abrogates B-cell death induced upon JAK2 inhibition. Thus, Theileria parasites ensure the survival of their host lymphocytes via specific activation of c-Myc.
引用
收藏
页码:1075 / 1083
页数:9
相关论文
共 35 条
[1]   The chromatin structure of the dual c-myc promoter P1/P2 is regulated by separate elements [J].
Albert, T ;
Wells, J ;
Funk, JO ;
Pullner, A ;
Raschke, EE ;
Stelzer, G ;
Meisterernst, I ;
Farnham, PJ ;
Eick, D .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2001, 276 (23) :20482-20490
[2]   Constitutive PI3-K activity is essential for proliferation, but not survival, of Theileria parva-transformed B cells [J].
Baumgartner, M ;
Chaussepied, M ;
Moreau, MF ;
Werling, D ;
Davis, WC ;
Garcia, A ;
Langsley, G .
CELLULAR MICROBIOLOGY, 2000, 2 (04) :329-339
[3]   Constitutive exclusion of Csk from Hck-positive membrane microdomains permits Src kinase-dependent proliferation of Theileria-transformed B lymphocytes [J].
Baumgartner, M ;
Angelisová, P ;
Setterblad, N ;
Mooney, N ;
Werling, D ;
Horejsí, V ;
Langsley, G .
BLOOD, 2003, 101 (05) :1874-1881
[4]   Stat3-mediated Myc expression is required for Src transformation and PDGF-induced mitogenesis [J].
Bowman, T ;
Broome, MA ;
Sinibaldi, D ;
Wharton, W ;
Pledger, WJ ;
Sedivy, JM ;
Irby, R ;
Yeatman, T ;
Courtneidge, SA ;
Jove, R .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2001, 98 (13) :7319-7324
[5]   Constitutive activation of Stat3 signaling confers resistance to apoptosis in human U266 myeloma cells [J].
Catlett-Falcone, R ;
Landowski, TH ;
Oshiro, MM ;
Turkson, J ;
Levitzki, A ;
Savino, R ;
Ciliberto, G ;
Moscinski, L ;
Fernández-Luna, JL ;
Nuñez, G ;
Dalton, WS ;
Jove, R .
IMMUNITY, 1999, 10 (01) :105-115
[6]   Inhibition of CK2 activity by TGF-β1 promotes IκB-α protein stabilization and apoptosis of immortalized hepatocytes [J].
Cavin, LG ;
Romieu-Mourez, R ;
Panta, GR ;
Sun, JY ;
Factor, VM ;
Thorgeirsson, SS ;
Sonenshein, GE ;
Arsura, M .
HEPATOLOGY, 2003, 38 (06) :1540-1551
[7]   Functional interaction of protein kinase CK2 and c-Myc in lymphomagenesis [J].
Channavajhala, P ;
Seldin, DC .
ONCOGENE, 2002, 21 (34) :5280-5288
[8]   Theileria transformation of bovine leukocytes: A parasite model for the study of lymphoproliferation [J].
Chaussepied, M ;
Langsley, G .
RESEARCH IN IMMUNOLOGY, 1996, 147 (03) :127-138
[9]   Upregulation of Jun and Fos family members and permanent JNK activity lead to constitutive AP-1 activation in Theileria-transformed leukocytes [J].
Chaussepied, M ;
Lallemand, D ;
Moreau, MF ;
Adamson, R ;
Hall, R ;
Langsley, G .
MOLECULAR AND BIOCHEMICAL PARASITOLOGY, 1998, 94 (02) :215-226
[10]   TNF-R1 signaling: A beautiful pathway [J].
Chen, GQ ;
Goeddel, DV .
SCIENCE, 2002, 296 (5573) :1634-1635