Human ubiquitous JCV(CY) T-antigen gene induces brain tumors in experimental animals

Abstract

JCV is a papovavirus which is widespread in the human population. The prototype Mad-1 variant of JCV induces a fatal demyelinating disease of the central nervous system (CNS) called Progressive Multifocal Leukoencephalopathy (PML) in immunosuppressed individuals. The unique tropism of JCV (Mad-1) to the CNS is attributed to the tissue-speci®c regulation of the viral early promoter which is responsible for the production of the viral regulatory protein, T-antigen. The archetype form of this virus, JCV(CY), which has been repeatedly isolated from the urine of PML and non-PML individuals, is distinct from JCV(Mad-1) in the structural organization of the regulatory sequence. To characterize the tissue speci®c expression of JCV(CY) and to investigate its potential in inducing disease, transgenic mice containing the early region of JCV(CY) were generated. Some of these mice between 9 ± 13 months of age exhibited signs of illness as manifested by paralysis of rear limbs, hunched posture, and poor grooming. Neuropathological examination indicated no sign of hypomyelination of the brain, but surprisingly, revealed the presence of primitive tumors originating from the cerebellum and the surrounding brain stem. The tumor masses also in®ltrated the surrounding tissue. Results from RNA and protein studies revealed a high level of Tantigen mRNA expression in hindbrains of clinically normal and aected transgenic mice. However, higher levels of T-antigen RNA and protein were detected in brains of the animals exhibiting severe illness. The close resemblance of JCV(CY) induced tumor in transgenic mice to the human medulloblastoma/primitive neuroectodermal tumor (PNETs) in location, histologic appearance, and expression of marker proteins strongly suggests the utility of this novel animal model for the study of human brain tumors.

Inhibition of IGF-I receptor in anchorage-independence attenuates GSK-3β constitutive phosphorylation and compromises growth and survival of medulloblastoma cell lines

“…The following cell lines were used in this study: mouse medulloblastoma, BsB8, isolated from cerebellar tumor of transgenic mouse expressing an early genome of human polyomavirus JC (Krynska et al, 1999;Wang et al, 2001); and two human medulloblastoma cell lines, D384 Med and Daoy. D384 are metastatic medulloblastomas isolated from peritoneal ascietes from a boy with medulloblastoma (ATCC# HTB-185), and Daoy derive from a tumor in the posterior fossa of a 4 years old boy (ATCC# HTB186).…”

Interaction between JCV large T-antigen and β-catenin

“…In earlier studies to unravel the biological function of JCV T-antigen, we created transgenic animals expressing the JCV early protein via the viral early promoter. Several lines developed tumors in the cerebellum, which were classified as medulloblastomas based on the location and expression of marker proteins (Krynska et al, 1999b). The expression of T-antigen was detected in tumor mass, and in cell lines derived from the tumor (Krynska et al, 2000).…”

IRS‐1–Rad51 nuclear interaction sensitizes JCV T‐antigen positive medulloblastoma cells to genotoxic treatment

“…[8][9][10][11] Of interest, PCR-based and immunohistochemical detection of the JC virus (JCV) genome and viral proteins, including JCV T-antigen, has raised questions about the contribution of this common polyomavirus to the development of medulloblastoma. [12][13][14][15] The genomic alterations and possible viral contribution suggest that mechanisms responsible for the maintenance of genomic integrity could be compromised in medulloblastomas. One feasible connection to the development of genomic instability is JCV Tantigen.…”

“…Although its role in the etiology of human tumors is still controversial, JCV T-antigen readily transforms cells in culture and is tumorigenic in experimental animals. 8,14,[16][17][18] In addition to the well-established effects of SV40, BKV and JCV T-antigens in deregulating the cell cycle, 19 these viral proteins are suspected to play a role in the development of genomic instability. Several studies have shown random chromosomal aberrations emerging at each consecutive passage of T-antigen positive cells.…”