Insulin-like growth factor I receptor signaling system in JC virus T antigen-induced primitive neuroectodermal tumors--medulloblastomas.
Medulloblastomas represent about 25% of all pediatric intracranial neoplasms. These highly malignant tumors arise from the cerebellum, affecting mainly children between ages 5 and 15. Although the etiology of medulloblastomas has not yet been elucidated, several reports suggest that both the cellular protein insulin-like growth factor I (IGF-I) and the early protein of the human polyomavirus JC (JCV T antigen) may contribute to the development of these tumors. The results of this study show a potential functional cooperation between these two proteins in the process of malignant transformation. Both medulloblastoma cell lines and medulloblastoma biopsies are characterized by the abundant presence of the IGF-I receptor (IGF-IR) and its major signaling molecule, insulin receptor substrate 1 (IRS-1). Importantly, IRS-1 is translocated to the nucleus in the presence of the JCV T antigen. Nuclear IRS-1 was detected in T antigen-positive cell lines and in T antigen-positive biopsies from patients diagnosed with medulloblastoma. The IRS-1 domain responsible for a direct JCV T antigen binding was localized within the N-terminal portion of IRS-1 molecule and the competition for IRS-1 T antigen binding by a dominant-negative mutant of IRS-1 inhibited growth and survival of JCV T antigen-transformed cells in anchorage-independent culture condition.
Del Valle
Luis
L
Center for Neurovirology and Cancer Biology, Temple University, Philadelphia, Pennsylvania 19122, USA.
Wang
Jin Ying
JY
Lassak
Adam
A
Peruzzi
Francesca
F
Croul
Sidney
S
Khalili
Kamel
K
Reiss
Krzysztof
K
D001932:Brain Neoplasms / Q000821:virology*; D002528:Cerebellar Neoplasms / Q000821:virology; D006801:Humans; D007577:JC Virus; D008527:Medulloblastoma / Q000821:virology; D018242:Neuroectodermal Tumors, Primitive / Q000821:virology*; D027601:Polyomavirus Infections / Q000150:complications / Q000503:physiopathology*; D017526:Receptor, IGF Type 1 / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D014412:Tumor Virus Infections / Q000150:complications / Q000503:physiopathology*
D017526:Receptor, IGF Type 1