Ca2+ responses in cytomegalovirus-infected fibroblasts of human origin

Nokta, Mostafa; Eaton, Douglas C.; Steinsland, Odd S.; Albrecht, Thomas

doi:10.1016/0042-6822(87)90268-6

Cited by 62 publications

(44 citation statements)

References 12 publications

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“…Calpain activity is associated with the propagation of Ca 2ϩ signaling (21), in some instances converting transient signals to more durable and amplified signals (92). It has been known for some time that HCMV infection induces a substantial increase in cytosolic Ca 2ϩ activity (58). The timing of the intracellular free Ca 2ϩ increase in HCMV-infected cells (58) is consistent with the increase in calpain activity illustrated in Fig.…”

Section: Analysis Of Pest Sequences In P21 Cip1supporting

confidence: 68%

“…These findings suggested that some additional MG132-insensitive pathway(s) may be involved in the proteolysis of p21 cip1 in HCMV-infected cells. As the unidentified mechanism(s) seemed to be quantitatively more important in p21 cip1 prote- fection induces substantial increases in intracellular free Ca 2ϩ (58) and in phospholipid degradation (1,2,81), raising the possibility that Ca 2ϩ -activated neutral proteases (calpains) might be activated by HCMV infection and participate in the proteolysis of p21 cip1 . Previous work has demonstrated that calpains are able to cleave cell cycle regulatory proteins, such as cyclin D1, cellular oncogene products (e.g., c-Mos, c-Jun, and c-Fos), and p53 (43,59; for reviews, see references 21 and 28).…”

Section: P21mentioning

confidence: 99%

“…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%

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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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Section: Analysis Of Pest Sequences In P21 Cip1supporting

confidence: 68%

Section: P21mentioning

confidence: 99%

Section: Kip1mentioning

confidence: 99%

See 1 more Smart Citation

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

Chen

Knutson

Kurosky

et al. 2001

J Virol

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“…To more precisely determine the phase of CMV-gene expression responsible for AA release, protein synthesis was blocked in infected cells with cycloheximide at Ϫ2 h and then released from the translational block in the presence or absence of functional transcriptional block (3Ј-deoxyadenosine) at 2 h PI. These conditions permit expression of CMV immediate early genes but not later genes when the CH block is released in the presence of 3Ј-deoxyadenosine (29). When the CH block is released in the absence of a transcriptional block, the early and late genes may then be expressed.…”

Section: Effect Of Anti-tnf-␣ Ab and Indomethacin On Cmv-mediated Supmentioning

confidence: 99%

Human cytomegalovirus-induced immunosuppression. Relationship to tumor necrosis factor-dependent release of arachidonic acid and prostaglandin E2 in human monocytes.

et al. 1996

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“…Although we are unaware of studies investigating ion shifts due to MCMV infection of brain cells, CMV infections of fibroblasts may increase cytoplasmic calcium, thereby possibly enhancing CMV replication (22). In the present study, we examined the changes in astrocyte Ca 2ϩ responses to glutamate, ATP, and depolarization by high K ϩ in the course of MCMV infection.…”

mentioning

confidence: 99%

Bystander Attenuation of Neuronal and Astrocyte Intercellular Communication by Murine Cytomegalovirus Infection of Glia

Pol

2007

J Virol

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Astrocytes are the first cells infected by murine cytomegalovirus (MCMV) in primary cultures of brain. These cells play key roles in intercellular signaling and neuronal development, and they modulate synaptic activity within the nervous system. Using ratiometric fura-2 digital calcium imaging of >8,000 neurons and glia, we found that MCMV-infected astrocytes showed an increase in intracellular basal calcium levels and an enhanced response to neuroactive substances, including glutamate and ATP, and to high potassium levels. Cultured neurons with no sign of MCMV infection showed attenuated synaptic signaling after infection of the underlying astrocyte substrate, and intercellular communication between astrocytes with no sign of infection was reduced by the presence of infected glia. These bystander effects would tend to cause further deterioration of cellular communication in the brain in addition to the problems caused by the loss of directly infected cells.

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Ca2+ responses in cytomegalovirus-infected fibroblasts of human origin

Cited by 62 publications

References 12 publications

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

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

Human cytomegalovirus-induced immunosuppression. Relationship to tumor necrosis factor-dependent release of arachidonic acid and prostaglandin E2 in human monocytes.

Bystander Attenuation of Neuronal and Astrocyte Intercellular Communication by Murine Cytomegalovirus Infection of Glia

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Ca2+ responses in cytomegalovirus-infected fibroblasts of human origin

Cited by 62 publications

References 12 publications

Degradation of p21 cip1 in Cells Productively Infected with Human Cytomegalovirus

Degradation of p21 cip1 in Cells Productively Infected with Human Cytomegalovirus

Human cytomegalovirus-induced immunosuppression. Relationship to tumor necrosis factor-dependent release of arachidonic acid and prostaglandin E2 in human monocytes.

Bystander Attenuation of Neuronal and Astrocyte Intercellular Communication by Murine Cytomegalovirus Infection of Glia

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

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