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Article
p53 signalling controls cell cycle arrest and caspase-independent apoptosis in macrophages infected with pathogenic Leptospira species
Cellular Microbiology
  • W. Huang
  • Yu-Mei Ge, Zhejiang University
  • David M. Ojcius, University of the Pacific
  • Dexter Sun, Cornell University
  • H. Dong
  • X. F. Yang
  • Jie Yan, Zhejiang University
ORCiD
David M. Ojcius: 0000-0003-1461-4495
Document Type
Article
DOI
10.1111/cmi.12141
Publication Date
10-1-2013
Abstract

Pathogenic Leptospira species, the causative agents of leptospirosis, have been shown to induce macrophage apoptosis through caspase-independent, mitochondrion-related apoptosis inducing factor (AIF) and endonuclease G (EndoG), but the signalling pathway leading to AIF/EndoG-based macrophage apoptosis remains unknown. Here we show that infection of Leptospira interrogans caused a rapid increase in reactive oxygen species (ROS), DNA damage, and intranuclear foci of 53BP1 and phosphorylation of H2AX (two DNAdamage indicators) in wild-type p53-containing mouse macrophages and p53-deficient human macrophages. Most leptospire-infected cells stayed at the G1 phase, whereas depletion or inhibition of p53 caused a decrease of the G1 -phase cells and the early apoptotic ratios. Infection with spirochaetes stimulated a persistent activation of p53 and an early activation of Akt through phosphorylation. The intranuclear translocation of p53, increased expression of p53-dependent p21(Cip) (1/) (WAF) (1) and pro-apoptotic Bcl-2 family proteins (Bax, Noxa and Puma), release of AIF and EndoG from mitochondria, and membrane translocation of Fas occurred during leptospire-induced macrophage apoptosis. Thus, our study demonstrated that ROS production and DNA damage-dependent p53-Bax/Noxa/Puma-AIF/EndoG signalling mediates the leptospire-induced cell cycle arrest and caspase-independent apoptosis of macrophages.

Citation Information
W. Huang, Yu-Mei Ge, David M. Ojcius, Dexter Sun, et al.. "p53 signalling controls cell cycle arrest and caspase-independent apoptosis in macrophages infected with pathogenic Leptospira species" Cellular Microbiology Vol. 15 Iss. 10 (2013) p. 1642 - 1659 ISSN: 1462-5814
Available at: http://works.bepress.com/david-ojcius/63/