Increased Levels of Sequence-Specific DNA-Binding Proteins in Human Cytomegalovirus-Infected Cells

Boldogh, István; Fons, M.; Albrecht, Thomas

doi:10.1006/bbrc.1993.2647

Cited by 31 publications

(34 citation statements)

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“…The fine tuning of AP-1 activity is important for flexible regulation of cell growth, differentiation and development in response to different stimuli. It has been reported previously that induction of c-fos and c-jun, the major subunits of AP-1, occurs after HCMV infection (Boldogh et al, 1990(Boldogh et al, , 1991(Boldogh et al, , 1993Hagemeier et al, 1992). AP-1 was found to be modulated in two phases during HCMV infection.…”

Section: Introductionmentioning

confidence: 93%

Human cytomegalovirus IE1 protein activates AP-1 through a cellular protein kinase(s).

Kim¹,

Lee

et al. 1999

Journal of General Virology

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Section: Introductionmentioning

confidence: 93%

Human cytomegalovirus IE1 protein activates AP-1 through a cellular protein kinase(s).

Kim¹,

Lee

et al. 1999

Journal of General Virology

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“…The subsequent calcium flow and PKC activation have been suggested to be involved in early activation of transcription factors interacting with DNA motifs, including B, CRE, and TPA-responsive element (23). In addition, the human CMV particle has been demonstrated to carry phosphatase activity (163) and to activate the membrane-proximal phospholipases C and A 2 as well as the MAP kinases extracellular signal-regulated kinases 1 and 2 (ERK1 and ERK2) and p38 immediately following infection (2,27,241).…”

Section: Cytomegalovirusmentioning

confidence: 99%

“…The rapid activation reported for human CMV infection (23) was not seen in murine CMV-infected macrophages (266). Another study showed that ATF/CRE-binding protein (CREB) DNA-binding activity was indeed induced following human CMV infection, but only at late time points after infection (121).…”

Section: Cytomegalovirusmentioning

confidence: 99%

Molecular Pathways in Virus-Induced Cytokine Production

Mogensen

Paludan

2001

Microbiol Mol Biol Rev

373

324

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Virus infections induce a proinflammatory response including expression of cytokines and chemokines. The subsequent leukocyte recruitment and antiviral effector functions contribute to the first line of defense against viruses. The molecular virus-cell interactions initiating these events have been studied intensively, and it appears that viral surface glycoproteins, double-stranded RNA, and intracellular viral proteins all have the capacity to activate signal transduction pathways leading to the expression of cytokines and chemokines. The signaling pathways activated by viral infections include the major proinflammatory pathways, with the transcription factor NF-κB having received special attention. These transcription factors in turn promote the expression of specific inducible host proteins and participate in the expression of some viral genes. Here we review the current knowledge of virus-induced signal transduction by seven human pathogenic viruses and the most widely used experimental models for viral infections. The molecular mechanisms of virus-induced expression of cytokines and chemokines is also analyzed

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“…Initially, HCMV infection induces a series of cellular responses that resemble the immediate-early events observed following activation of serumarrested cells by serum growth factors (4). These include hydrolysis of phosphatidylinositol 4,5-bisphosphate, yielding increased cellular levels of sn-1,2-diacylglycerol (DG) and inositol 1,4,5-trisphosphate (81); increased release of arachidonic acid and its metabolites (1,2); changes in Ca 2ϩ homeostasis, including Ca 2ϩ influx, release of Ca 2ϩ stores, and an increase in intracellular free Ca 2ϩ (58); transcriptional activation of cellular oncogenes c-fos, c-jun, and c-myc (11,12,13); and increased activity of the DNA-binding proteins NFB, AP-1, and CREB (14). The signaling cascade induced by HCMV infection induces a robust mitogenic response, as evidenced by the ability of HCMV to stimulate cell cycle entry by densityarrested cells, which are resistant to stimulation by serum growth factors (19).…”

Section: Kip1mentioning

confidence: 99%

Degradation of p21 ^cip1 in Cells Productively Infected with Human Cytomegalovirus

Chen

Knutson

Kurosky

et al. 2001

J Virol

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Human cytomegalovirus (HCMV) stimulates arrested cells to enter the cell cycle by activating cyclindependent kinases (Cdks), notably Cdk2. Several mechanisms are involved in the activation of Cdk2. HCMV causes a substantial increase in the abundance of cyclin E and stimulates translocation of Cdk2 from the cytoplasm to the nucleus. Further, the abundance of the Cdk inhibitors (CKIs) p21 cip1/waf1 (p21 cip1 ) and p27 kip1 is substantially reduced. The activity of cyclin E/Cdk2 increases as levels of CKIs, particularly p21 cip1 , fall. We have previously shown that these phenomena contribute to priming the cell for efficient replication of HCMV. In this study, the mechanisms responsible for the decrease in p21 cip1 levels after HCMV infection were investigated by measuring p21 cip1 RNA and protein levels in permissive human lung (LU) fibroblasts after HCMV infection. Northern blot analysis revealed that p21 cip1 RNA levels increased briefly at 3 h after HCMV infection and then decreased to their nadir at 24 h; thereafter, RNA levels increased to about 60% of the preinfection level. Western blot analysis demonstrated that the relative abundance of p21 cip1 protein roughly paralleled the observed changes in initial RNA levels; however, the final levels of protein were much lower than preinfection levels. After a transient increase at 3 h postinfection, p21 cip1 abundance declined sharply over the next 24 h and remained at a very low level through 96 h postinfection. The disparity between p21 cip1 RNA and protein levels suggested that the degradation of p21 cip1 might be affected in HCMV-infected cells. Treatment of HCMV-infected cells with MG132, an inhibitor of proteasome-mediated proteolysis, provided substantial protection of p21 cip1 in mock-infected cells, but MG132 was much less effective in protecting p21 cip1 in HCMV-infected cells. The addition of E64d or Z-Leu-Leu-H, each an inhibitor of calpain activity, to HCMVinfected cells substantially increased the abundance of p21 cip1 in a concentration-dependent manner. To verify that p21 cip1 was a substrate for calpain, purified recombinant p21 cip1 was incubated with either m-calpain or -calpain, which resulted in rapid proteolysis of p21 cip1 . E64d inhibited the proteolysis of p21 cip1 catalyzed by either m-calpain or -calpain. Direct measurement of calpain activity in HCMV-infected LU cells indicated that HCMV infection induced a substantial and sustained increase in calpain activity, although there was no change in the abundance of either m-or -calpain or the endogenous calpain inhibitor calpastatin. The observed increase of calpain activity was consistent with the increases in intracellular free Ca 2؉ and phospholipid degradation in HCMV-infected LU cells reported previously from our laboratory. Considered together, these results suggest that the increase in calpain activity observed following HCMV infection contributes significantly to the reduction of p21 cip1 levels and the resultant cell cycle progression.Human cytomegalovirus (HCMV) infection is wides...

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Increased Levels of Sequence-Specific DNA-Binding Proteins in Human Cytomegalovirus-Infected Cells

Cited by 31 publications

References 0 publications

Human cytomegalovirus IE1 protein activates AP-1 through a cellular protein kinase(s).

Human cytomegalovirus IE1 protein activates AP-1 through a cellular protein kinase(s).

Molecular Pathways in Virus-Induced Cytokine Production

Degradation of p21 ^cip1 in Cells Productively Infected with Human Cytomegalovirus

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Increased Levels of Sequence-Specific DNA-Binding Proteins in Human Cytomegalovirus-Infected Cells

Cited by 31 publications

References 0 publications

Human cytomegalovirus IE1 protein activates AP-1 through a cellular protein kinase(s).

Human cytomegalovirus IE1 protein activates AP-1 through a cellular protein kinase(s).

Molecular Pathways in Virus-Induced Cytokine Production

Degradation of p21 cip1 in Cells Productively Infected with Human Cytomegalovirus

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Degradation of p21 ^cip1 in Cells Productively Infected with Human Cytomegalovirus