T-antigen of human polyomavirus JC cooperates withIGF-IR signaling system in cerebellar tumors of the childhood-medulloblastomas.
Polyomaviruses are implicated in a number of cancers, and the transforming activity of their early protein, large T-antigen, has been documented in a variety of cell types and in experimental animals (1). Although the pathways by which T-antigen induces uncontrolled cell growth are not fully defined, T-antigen mediated inactivation of tumor suppressors, p53 and pRB, is well-documented in some malignancies (2). Here we postulate that functional interaction between the insulin-like growth factor (IGF-IR) and the T-antigen of human polyomavirus JC (JCV T-antigen) may contribute to the process of malignant transformation in medulloblastomas: (i) the IGF-IR signaling system is strongly activated in medulloblastoma cell lines and medulloblastoma biopsies; (ii) the cytoplasmic protein, insulin receptor substrate 1 (IRS-1), is translocated to the nucleus in the presence of JCV T-antigen; (iii) molecular characterization of the interaction between IRS-1 and JCV T-antigen indicates that the binding involves the N-terminal portion of IRS-1 (PH/PTB domain) and the C-terminal region of JCV T-antigen (aa 411-628); and finally (iv) competition for the IRS-1-JCV T-antigen binding attenuates anchorage-independent growth of T-antigen positive medulloblastoma cells in culture. Based on these findings, we propose a novel role for IRS-1 in JCV T-antigen-mediated deregulation of cellular equilibrium, which may involve uncoupling of IRS-1 from the surface receptor and translocation of its function to the nuclear compartment of the cell.
Khalili
Kamel
K
Center for Neurovirology and Cancer Biology, Temple University, 1900 North 12th Street, Philadelphia, PA 19122, USA.
Del Valle
Luis
L
Wang
Jin Ying
JY
Darbinian
Nune
N
Lassak
Adam
A
Safak
Mahmut
M
Reiss
Krzysztof
K
D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000378:metabolism / Q000502:physiology*; D002528:Cerebellar Neoplasms / Q000276:immunology* / Q000821:virology*; D002648:Child; D006801:Humans; D007577:JC Virus / Q000276:immunology*; D008527:Medulloblastoma / Q000276:immunology* / Q000821:virology*; D051379:Mice; D017526:Receptor, IGF Type 1 / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology
D000952:Antigens, Polyomavirus Transforming; D017526:Receptor, IGF Type 1