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.

Human retinoblastoma is not caused by known pRb‐inactivating human DNA tumor viruses

“…2 In addition to mutations in the RB1 gene, pRb function can be abrogated by oncoproteins from several DNA tumor viruses that infect humans. 3 HAdV E1A, the E7 protein of highrisk human papillomaviruses (HPV), and the large T-antigens from BKV, JCV and SV40 have all been demonstrated to bind to pRb through a homologous pRb binding domain [4][5][6] and inactivate pRb by various mechanisms. 3 Retinoblastomas have been observed in transgenic mice that express HPV16 E7 7 or SV40 Tantigen, 2 in hamsters inoculated intraocularly with JCV and in primates infected with HAdV 12.…”

Interaction of retinoblastoma protein family members with large T-antigen of primate polyomaviruses

“…The role of the interaction of pRb in JCV T-antigeninduced tumorigenesis has been investigated in a transgenic mouse model (Krynska et al, 1997). Transgenic mice harboring the JCV early genome develop tumors of neural crest origin which express high levels of JCV large T-antigen.…”

Pituitary neoplasia induced by expression of human neurotropic polyomavirus, JCV, early genome in transgenic mice

“…Several recent studies have focused on the role of T-antigen in tumorigenesis and the cellular pathways by which JCV may be involved in transformation and tumor formation. In JCV-induced neuroectodermal-origin tumors JCV T-antigen was found in complex with p53, and the level of p21/ WAF-1, a downstream target of p53 which controls the G1 to S phase transition of the cell cycle, was decreased (Krynska et al, 1997).…”