ROLE OF CELL-CYCLE REGULATORS IN TUMOR-FORMATION IN TRANSGENIC MICE EXPRESSING THE HUMAN NEUROTROPIC VIRUS, JCV, EARLY PROTEIN

Transgenic mice harboring the early genome from the human neurotropic JC virus, ICV, 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 tr ansform 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 cont rols 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 lever of expression and activity of cyclin D1 and its associated kinase, cdk6, was modest in tumor cells, both cycl in A and E, and their kinase partners, cdk2 and cdk4, were highly expr essed and exhibited significant kinase activity. The retinoblastoma ge ne product, pRb, which upon phosphorylation by cyclins:cdk induces rap id cell proliferation, was found in the phosphorylated slate in tumor cell extracts, and was detected in association with ICV T-antigen. The transcription factor, E2F-1, which dissociates from the pRb-E2F-1 com plex and stimulates S phase-specific genes upon phosphorylation of pRb and/or complexation of pRb with the viral transforming protein, was h ighly 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 potentia l regulating pathway that, upon expression of ICV T-antigen, induces f ormation and progression of tumors of neural origin in a whole animal system. (C) 1997 Wiley-Liss, Inc.