title: Small molecule inhibitors of the host cell COX/AREG/EGFR/ERK pathway attenuate cytomegalovirus-induced pathogenesis.
abstract: As with other herpesviruses, human cytomegalovirus (hCMV) has the ability to establish lifelong persistence and latent infection following primary exposure, salivary glands (SMGs) being the primary site of both. In the immunocompromised patient, hCMV is a common cause of opportunistic infections, and subsequent morbidity and mortality. Elucidating the molecular pathogenesis of CMV-induced disease is critical to the development of more effective and safer drug therapies. In the present study, we used a novel mouse postnatal SMG organ culture model of mCMV-induced dysplasia to investigate a candidate signaling network suggested by our prior studies (COX-2/AREG/EGFR/ERK). The objective was to employ small molecule inhibitors to target several key steps in the autocrine loop, and in this way ameliorate pathology. Our results indicate that upregulation of ERK phosphorylation is necessary for initial mCMV-induced pathogenesis, and that ErbB receptor family phosphorylation and downstream signaling are highly relevant targets for drug discovery.
authors.affiliation: Laboratory for Developmental Genetics, USC, Los Angeles, CA 90089-0641, USA. mmelnick@usc.edu
authors.forename: Michael
authors.initials: M
authors.lastname: Melnick
authors.forename: George
authors.initials: G
authors.lastname: Abichaker
authors.forename: Khine
authors.initials: K
authors.lastname: Htet
authors.forename: Parish
authors.initials: P
authors.lastname: Sedghizadeh
authors.forename: Tina
authors.initials: T
authors.lastname: Jaskoll
mesh_terms: D066258:Amphiregulin; D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western; D002070:Butadienes / Q000494:pharmacology; D049109:Cell Proliferation; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004008:Diclofenac / Q000494:pharmacology; D004195:Disease Models, Animal; D066255:EGF Family of Proteins; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D006023:Glycoproteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006566:Herpesviridae Infections / Q000378:metabolism / Q000517:prevention & control* / Q000821:virology; D054884:Host-Pathogen Interactions; D007124:Immunoenzyme Techniques; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018146:Muromegalovirus / Q000472:pathogenicity*; D009570:Nitriles / Q000494:pharmacology; D009924:Organ Culture Techniques; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013363:Submandibular Gland / Q000821:virology
chemical_list: C587848:AREG protein, human; D066258:Amphiregulin; C587849:Areg protein, mouse; D002070:Butadienes; D016861:Cyclooxygenase Inhibitors; D066255:EGF Family of Proteins; D004791:Enzyme Inhibitors; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D009570:Nitriles; C113580:U 0126; D004008:Diclofenac; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D066246:ErbB Receptors; D048052:Mitogen-Activated Protein Kinase 3