Control of apoptosis in influenza virus-infected cells by up-regulation of Akt and p53 signaling |
| |
Authors: | Oleg P Zhirnov Hans-Dieter Klenk |
| |
Institution: | (1) D.I. Ivanovsky Institute of Virology, Moscow, 123098, Russia;(2) Institute of Virology, Philipps University of Marburg, Marburg, 35043, Germany |
| |
Abstract: | PI3k-Akt and p53 pathways are known to play anti- and pro-apoptotic roles in cell death, respectively. Whether these pathways
are recruited in influenza virus infection in highly productive monkey (CV-1) and canine (MDCK) kidney cells was studied here.
Phosphorylation of Akt (Akt-pho) was found to occur only early after infection (5–9 h.p.i). Nuclear accumulation and phosphorylation
of p53 (p53-pho), and expression of its natural target p21/waf showed low constitutive levels at this period, whereas all
three parameters were markedly elevated at the late apoptotic stage (17–20 h.p.i.). Up-regulation of Akt-pho and p53-pho was
not induced by UV-inactivated virus suggesting that it required virus replication. Also, mRNAs of p53 and its natural antagonist
mdm2 were not increased throughout infection indicating that p53-pho was up-regulated by posttranslational mechanisms. However,
p53 activation did not seem to play a leading role in influenza-induced cell death: (i) infection of CV1 and MDCK cells with
recombinant NS1-deficient virus provoked accelerated apoptotic death characterized by the lack of p53 activation; (ii) mixed
apoptosis-necrosis death developed in influenza-infected human bronchial H1299 cells carrying a tetracycline-regulated p53
gene did not depend on p53 gene activation by tetracycline. Virus-induced apoptosis and signaling of Akt and p53 developed
in IFN-deficient VERO cells with similar kinetics as in IFN-competent CV1-infected cells indicating that these processes were
endocrine IFN-independent. Apoptosis in influenza-infected CV-1 and MDCK cells was Akt-dependent and was accelerated by Ly294002,
a specific inhibitor of PI3k-Akt signaling, and down-regulated by the viral protein NS1, an inducer of host Akt. The obtained
data suggest that influenza virus (i) initiates anti-apoptotic PI3k-Akt signaling at early and middle phases of infection
to protect cells from fast apoptotic death and (ii) provokes both p53-dependent and alternative p53-independent apoptotic
and/or necrotic (in some host systems) cell death at the late stage of infection.
These data have been partially presented at The 3rd Orthomyxovirus Research Conference (sponsored by ESWI and NIH). Abstr.
p. 23 entitled: “Influenza virus-specific up-regulation of Akt and Mdm2 in infected cells” by Zhirnov O.P., and Klenk H.D.,
July 28–21, 2005. Queen’s College, Cambridge, United Kingdom; and at The Annual Meeting of Virology in Munich, March 15–18
(2006)—“Influenza virus-specific up-regulation of Akt, Mdm2, and p53 in infected cells” by O. P. Zhirnov and H. D. Klenk;
Book of abstracts, p. 339 |
| |
Keywords: | Influenza virus Apoptosis Akt p53 |
本文献已被 PubMed SpringerLink 等数据库收录! |
|