Activating transcription factor 4 (ATF4) is upregulated by human herpesvirus 8 infection, increases virus replication and promotes proangiogenic properties.
Human herpesvirus 8 (HHV-8) triggers proangiogenic behaviour in endothelial cells by inducing monocyte chemoattractant protein 1 (MCP-1) through activation of Nuclear Factor κB (NF-κB). However, NF-κB inhibition still results in partial MCP-1 induction and consequent angiogenesis, suggesting the involvement of another transcriptional pathway. We analysed activating transcription factor 4 (ATF4), since it is central in the cellular response to stress and is involved in angiogenesis. The results show that HHV-8 upregulates ATF4 expression, which in turn promotes HHV-8 infection, and induces MCP-1 production and proangiogenic properties in endothelial cells. By contrast, ATF4 silencing decreases virus replication and inhibits virus-induced MCP-1 production and induction of tube-like structures. Therefore, ATF4 plays a role in HHV-8 replication and associated virus-induced angiogenesis. The elucidation of molecular pathways involved in this process will result in a better understanding of the virus-induced angiogenic process and might help in designing novel therapies to reduce tumour growth.
Section of Microbiology, Department of Experimental and Diagnostic Medicine, University of Ferrara, via L. Borsari 46, 44100 Ferrara, Italy. csb@unife.it
Elisabetta
E
Caselli
Sabrina
S
Benedetti
Jessica
J
Grigolato
Arnaldo
A
Caruso
Dario
D
Di Luca
D051701:Activating Transcription Factor 4 / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism / Q000821:virology; D006566:Herpesviridae Infections / Q000235:genetics* / Q000378:metabolism / Q000821:virology; D019288:Herpesvirus 8, Human / Q000235:genetics / Q000502:physiology*; D006801:Humans; D009389:Neovascularization, Pathologic / Q000235:genetics* / Q000378:metabolism / Q000821:virology; D015533:Transcriptional Activation; D015854:Up-Regulation; D014779:Virus Replication
D018932:Chemokine CCL2; D051701:Activating Transcription Factor 4