title: Role of cell cycle regulators in tumor formation in transgenic mice expressing the human neurotropic virus, JCV, early protein.
abstract: Transgenic mice harboring the early genome from the human neurotropic JC virus, JCV, develop massive abdominal tumors of neural crest origin during 6-8 months after birth and succumb to death a few weeks later. The viral early protein, T-antigen, which possesses the ability to transform cells of neural origin, is highly expressed in the tumor cells. Immunoblot analysis of protein extract from tumor tissue shows high level expression of the tumor suppressor protein, p53, in complex with T-antigen. Expression of p21, a downstream target for p53, which controls cell cycle progression by regulating the activity of cyclins and their associated kinases during the G1 phase, is extremely low in the tumor cells. Whereas the level of expression and activity of cyclin D1 and its associated kinase, cdk6, was modest in tumor cells, both cyclin A and E, and their kinase partners, cdk2 and cdk4, were highly expressed and exhibited significant kinase activity. The retinoblastoma gene product, pRb, which upon phosphorylation by cyclins:cdk induces rapid cell proliferation, was found in the phosphorylated state in tumor cell extracts, and was detected in association with JCV T-antigen. The transcription factor, E2F-1, which dissociates from the pRb-E2F-1 complex and stimulates S phase-specific genes upon phosphorylation of pRb and/or complexation of pRb with the viral transforming protein, was highly expressed in tumor cells. Accordingly, high level expression of the E2F-1-responsive gene, proliferating cell nuclear antigen (PCNA), was detected in the tumor cells. These observations suggest a potential regulating pathway that, upon expression of JCV T-antigen, induces formation and progression of tumors of neural origin in a whole animal system.
authors.affiliation: Centre for NeuroVirology and NeuroOncology, Allegheny University of the Health Sciences, Philadelphia, Pennsylvania 19102, USA.
authors.forename: B
authors.initials: B
authors.lastname: Krynska
authors.forename: J
authors.initials: J
authors.lastname: Gordon
authors.forename: J
authors.initials: J
authors.lastname: Otte
authors.forename: R
authors.initials: R
authors.lastname: Franks
authors.forename: R
authors.initials: R
authors.lastname: Knobler
authors.forename: A
authors.initials: A
authors.lastname: DeLuca
authors.forename: A
authors.initials: A
authors.lastname: Giordano
authors.forename: K
authors.initials: K
authors.lastname: Khalili
mesh_terms: D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000235:genetics* / Q000378:metabolism; D042846:CDC2-CDC28 Kinases; D019925:Cyclin A / Q000235:genetics / Q000378:metabolism; D019927:Cyclin E / Q000235:genetics / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D016213:Cyclins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015870:Gene Expression; D006801:Humans; D007577:JC Virus / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D009380:Neoplasms, Nerve Tissue / Q000737:chemistry / Q000235:genetics*; D010766:Phosphorylation; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D016160:Retinoblastoma Protein / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D000952:Antigens, Polyomavirus Transforming; C493956:CDKN1A protein, human; C493957:Cdkn1a protein, mouse; D019925:Cyclin A; D019927:Cyclin E; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D018809:Proliferating Cell Nuclear Antigen; D011518:Proto-Oncogene Proteins; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; C495900:CDK4 protein, human; C495893:Cdk2 protein, mouse; C495902:Cdk4 protein, mouse; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases