title: Human cytomegalovirus immediate early proteins promote degradation of connexin 43 and disrupt gap junction communication: implications for a role in gliomagenesis.
abstract: A lack of gap junctional intercellular communication (GJIC) is common in cancer. Many oncogenic viruses have been shown to downregulate the junctional protein connexin 43 (Cx43) and reduce GJIC. Human cytomegalovirus (HCMV) is a ubiquitous, species-specific betaherpesvirus that establishes life-long latency after primary infection. It encodes two viral gene products, immediate early (IE) proteins IE1 and IE2, which are crucial in viral replication and pathogenesis of many diseases. Emerging evidence demonstrates that HCMV DNA and proteins are highly prevalent in glioblastoma multiforme (GBM) and in other tumors, but HCMV's role in tumorigenesis remains obscure. In the present study, we examined the effects of HCMV infection on Cx43 expression and GJIC as well as the viral mechanism mediating the effects in human GBM cells and tissue samples. We found that HCMV downregulated Cx43 protein, resulting in disruption of functional GJIC as assayed by fluorescent dye transfer assay. We show that both HCMV-IE72 and IE86 mediate downregulation of Cx43 by silencing RNA targeting either IE72 or IE86 coupled with ganciclovir. This finding was further validated by transfection with expression vectors encoding IE72 or IE86, and we show that viral-mediated Cx43 depletion involved proteasomal degradation. Importantly, we also observed that the Cx43 protein levels and IE staining correlated inversely in 10 human GBM tissue specimens. Thus, HCMV regulates Cx43 expression and GJIC, which may contribute to gliomagenesis.
authors: Department of Medicine, Solna, Unit for Experimental Cardiovascular Research, Center for Molecular Medicine, Karolinska Institutet, Stockholm SE-171 76, Sweden and.
authors: Zahidul
authors: Z
authors: Khan
authors: Koon-Chu
authors: KC
authors: Yaiw
authors: Vanessa
authors: V
authors: Wilhelmi
authors: Hoyin
authors: H
authors: Lam
authors: Afsar
authors: A
authors: Rahbar
authors: Giuseppe
authors: G
authors: Stragliotto
authors: Cecilia
authors: C
authors: Söderberg-Nauclér
mesh_terms: D016543:Central Nervous System Neoplasms / Q000473:pathology / Q000821:virology*; D018031:Connexin 43 / Q000235:genetics / Q000378:metabolism*; D003587:Cytomegalovirus / Q000378:metabolism / Q000472:pathogenicity; D003586:Cytomegalovirus Infections / Q000150:complications / Q000378:metabolism* / Q000821:virology; D005347:Fibroblasts / Q000378:metabolism / Q000821:virology; D017629:Gap Junctions / Q000378:metabolism*; D005909:Glioblastoma / Q000473:pathology / Q000821:virology*; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D018031:Connexin 43; C500216:GJA1 protein, human; C088645:IE1 protein, cytomegalovirus; C069186:IE2 protein, Cytomegalovirus; D017874:Immediate-Early Proteins; D015534:Trans-Activators; D046988:Proteasome Endopeptidase Complex