A Mitogenic Signal Triggered at an Early Stage of Vaccinia Virus Infection

Abstract

Vaccinia virus (VV) triggers a mitogenic signal at an early stage of infection. VV-induced proto-oncogene c-fos mRNA with kinetics paralleling that stimulated by serum. The VV virokine, or vaccinia virus growth factor (VGF), was not crucial for c-fos induction because it was observed upon infection with the virokine-minus mutant VV (VGF ؊ ). Furthermore, c-fos expression did not require infectious virus particles, as it occurred even with UV-inactivated VV and was equally induced by the different multiplicities of infection, i.e. 1.0, 5.0, and 25.0. c-fos expression was preceded by VV-induced DNA binding activity and was mediated via the cis-acting elements serum response element (SRE), activating protein-1 (AP-1), and cAMP-response element (CRE). VV activated the protein kinases p42MAPK/ERK2 and p44MAPK/ERK1 and the transcription factor ATF1 in a time-dependent manner with kinetics that paralleled those of VV-stimulated DNAprotein complex formation. The mitogenic signal transmission pathways leading to c-fos activation upon VV infection were apparently mediated by the protein kinases MEK, ERK, and PKA. This assumption was based on the findings that: 1) c-fos transcript was down-regulated; 2) the SRE, AP-1, and CRE binding activities were significantly reduced; and 3) the activation of p42MAPK/ERK2, p44MAPK/ERK1, and ATF1 were drastically affected when the viral infections were carried out in the presence of specific protein kinase inhibitor. Moreover, the mutant VV (VGF ؊ ) was also able to activate ERK1/2. It is noteworthy that virus multiplication was equally affected by the same kinase inhibitors. Taken together, our data provide evidence that the early mitogenic signal triggered upon VV infection relies upon the activation of the protein kinases MEK, ERK, and PKA, which are needed for both signal transduction and virus multiplication.

Eukaryotic Translation Initiation Factor 4F Architectural Alterations Accompany Translation Initiation Factor Redistribution in Poxvirus-Infected Cells

“…4A) or murine cells (not shown). Our observations for primary human cells agree with other reports using established cell lines (4,11,24). However, in addition to activating ERK and p38, eIF4E phosphorylation requires eIF4F assembly, illustrating the requirement for proper complex architecture to ensure that the activated kinase Mnk1 is properly oriented in respect to its substrate, eIF4E (35,43,47).…”

Primary Human Macrophages Serve as Vehicles for Vaccinia Virus Replication and Dissemination

“…GM-CSF receptor activation is followed by Jak2 phosphorylation of receptor tyrosines and eventual activation of Stat5 and the MAPK pathways via Grb2, Shc, and SHP2 (66). Similarly, VACV is reported to be dependent on MAPK signaling for replication (45,46,47). We observed significantly decreased viral production with treatment of Akt and Erk inhibitors (Fig.…”

“…VACV is dependent on Akt and Erk1/2 signaling pathways for entry and replication (45)(46)(47)(48). Since we have discovered that M1 and M2 cells are permissive to VACV, we sought to analyze the dependence of these two pathways on VACV replication in MDMs independent of binding and entry.…”

Intracellular Transport of Vaccinia Virus in HeLa Cells Requires WASH-VPEF/FAM21-Retromer Complexes and Recycling Molecules Rab11 and Rab22

“…Vaccinia MV enters cells through either endocytosis or plasma membrane fusion, depending on the involved virus strain (6,(8)(9)(10)51) and the cell type (7,22,(52)(53)(54). We previously showed that vaccinia MV of the WR strain enters HeLa and MEF cells through fluid-phase endocytosis, after which the internalized MV particles associate with PI3P-positive macropinosomes and Rab5-positive endosomes (19,20).…”