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

The large T‐antigen from human polyomavirus JC (JCV T‐antigen) is suspected to play a role in malignant transformation. Previously, we reported that JCV T‐antigen requires the presence of a functional insulin‐like growth factor I receptor (IGF‐IR) for transformation of fibroblasts and for survival of medulloblastoma cell lines; that IGF‐IR is phosphorylated in medulloblastoma biopsies and that JCV T‐antigen inhibits homologous recombination‐directed DNA repair, causing accumulation of mutations. Here we are evaluating whether JCV T‐antigen positive and negative mouse medulloblastoma cell lines, which significantly differ in their tumorigenic properties, are also different in their abilities to repair double strand breaks of DNA (DSBs). Our results show that despite much stronger tumorigenic potential, JCV T‐antigen positive medulloblastoma cells are more sensitive to genotoxic agents (cisplatin and γ‐irradiation). Subsequent analysis of DNA repair of DSBs indicated that homologous recombination‐directed DNA repair (HRR) was selectively attenuated in JCV T‐antigen positive medulloblastoma cells. JCV T‐antigen did not affect HRR directly. In the presence of JCV T‐antigen, insulin receptor substrate 1 (IRS‐1) translocated to the nucleus where it co‐localized with Rad51, possibly attenuating HRR. © 2006 Wiley‐Liss, Inc.

[1]  S. Croul,et al.  T‐antigen of the human polyomavirus JC attenuates faithful DNA repair by forcing nuclear interaction between IRS‐1 and Rad51 , 2006, Journal of cellular physiology.

[2]  L. Wiesmüller,et al.  Differences in the association of p53 phosphorylated on serine 15 and key enzymes of homologous recombination , 2005, Oncogene.

[3]  T. Tamiya,et al.  Detection of JC virus DNA sequences in brain tumors in pediatric patients. , 2005, Journal of neurosurgery.

[4]  Jean Hou,et al.  Investigation of human brain tumors for the presence of polyomavirus genome sequences by two independent laboratories , 2005, International journal of cancer.

[5]  H. Parkman,et al.  Detection of JC virus DNA sequences and expression of viral T antigen and agnoprotein in esophageal carcinoma , 2005, Cancer.

[6]  R. Baserga,et al.  Regulation of Upstream Binding Factor 1 Activity by Insulin-like Growth Factor I Receptor Signaling* , 2005, Journal of Biological Chemistry.

[7]  Douglas C. Miller,et al.  Feasibility and response to induction chemotherapy intensified with high-dose methotrexate for young children with newly diagnosed high-risk disseminated medulloblastoma. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[8]  A. Giordano,et al.  Polyomaviruses and cancer--interplay between viral proteins and signal transduction pathways. , 2004, Journal of experimental & clinical cancer research : CR.

[9]  R. Baserga,et al.  Control of cell size through phosphorylation of upstream binding factor 1 by nuclear phosphatidylinositol 3-kinase. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[10]  Y. Saintigny,et al.  p53's double life: transactivation-independent repression of homologous recombination. , 2004, Trends in genetics : TIG.

[11]  K. Khalili,et al.  HIV-1 Tat increases cell survival in response to cisplatin by stimulating Rad51 gene expression , 2004, Oncogene.

[12]  K. Khalili,et al.  Role of the Insulin-Like Growth Factor I/Insulin Receptor Substrate 1 Axis in Rad51 Trafficking and DNA Repair by Homologous Recombination , 2003, Molecular and Cellular Biology.

[13]  F. Bazzoli,et al.  Induction of chromosomal instability in colonic cells by the human polyomavirus JC virus. , 2003, Cancer research.

[14]  K. Khalili,et al.  T-antigen of human polyomavirus JC cooperates withIGF-IR signaling system in cerebellar tumors of the childhood-medulloblastomas. , 2003, Anticancer research.

[15]  S. Croul,et al.  Insulin-like growth factor I receptor signaling system in JC virus T antigen-induced primitive neuroectodermal tumors--medulloblastomas. , 2002, Journal of neurovirology.

[16]  I. Casaburi,et al.  Nuclear Translocation of Insulin Receptor Substrate-1 by Oncogenes And Igf-I , 2002, The Journal of Biological Chemistry.

[17]  K. Khalili,et al.  Detection of JC polyomavirus DNA sequences and cellular localization of T-antigen and agnoprotein in oligodendrogliomas. , 2002, Clinical cancer research : an official journal of the American Association for Cancer Research.

[18]  K. Reiss.  Insulin-like growth factor-I receptor – a potential therapeutic target in medulloblastomas , 2002, Expert opinion on therapeutic targets.

[19]  L. Wiesmüller,et al.  DNA Substrate Dependence of p53-Mediated Regulation of Double-Strand Break Repair , 2002, Molecular and Cellular Biology.

[20]  R. Baffa,et al.  Nuclear Translocation of Insulin Receptor Substrate-1 by the Simian Virus 40 T Antigen and the Activated Type 1 Insulin-like Growth Factor Receptor* , 2002, The Journal of Biological Chemistry.

[21]  S. Croul,et al.  Insulin Receptor Substrate 1 Translocation to the Nucleus by the Human JC Virus T-antigen* , 2002, The Journal of Biological Chemistry.

[22]  G. Reifenberger,et al.  The WHO Classification of Tumors of the Nervous System , 2002, Journal of neuropathology and experimental neurology.

[23]  S. Croul,et al.  Expression of human neurotropic polyomavirus JCV late gene product agnoprotein in human medulloblastoma. , 2002, Journal of the National Cancer Institute.

[24]  K. Khalili,et al.  Human Polyomaviruses: Molecular and Clinical Perspectives , 2002 .

[25]  P. Labhart,et al.  Nonhomologous DNA end joining in cell-free systems. , 2001, European journal of biochemistry.

[26]  S. Croul,et al.  Activation of the IGF-IR system contributes to malignant growth of human and mouse medulloblastomas , 2001, Oncogene.

[27]  J. Hoeijmakers.  Genome maintenance mechanisms for preventing cancer , 2001, Nature.

[28]  S. Croul,et al.  Detection of JC virus DNA sequences and expression of the viral regulatory protein T-antigen in tumors of the central nervous system. , 2001, Cancer research.

[29]  K. Khanna,et al.  DNA double-strand breaks: signaling, repair and the cancer connection , 2001, Nature Genetics.

[30]  R. Frisque,et al.  Purified JC virus T and T' proteins differentially interact with the retinoblastoma family of tumor suppressor proteins. , 2000, Virology.

[31]  S. Croul,et al.  Identification of a novel p53 mutation in JCV-induced mouse medulloblastoma. , 2000, Virology.

[32]  J. Pipas,et al.  Species-Specific Elements in the Large T-Antigen J Domain Are Required for Cellular Transformation and DNA Replication by Simian Virus 40 , 2000, Molecular and Cellular Biology.

[33]  V. Yamazaki,et al.  A critical role for histone H2AX in recruitment of repair factors to nuclear foci after DNA damage , 2000, Current Biology.

[34]  M. Hrabě de Angelis,et al.  Comet assay as a tool to screen for mouse models with inherited radiation sensitivity , 2000, Mammalian Genome.

[35]  B. Geoerger,et al.  Autocrine secreted insulin-like growth factor-I stimulates MAP kinase-dependent mitogenic effects in human primitive neuroectodermal tumor/medulloblastoma. , 2000, International journal of oncology.

[36]  L. Thompson,et al.  XRCC3 promotes homology-directed repair of DNA damage in mammalian cells. , 1999, Genes & development.

[37]  J Gordon,et al.  Detection of human neurotropic JC virus DNA sequence and expression of the viral oncogenic protein in pediatric medulloblastomas. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[38]  H. Scherthan,et al.  Chromosomal imbalances and DNA amplifications in SV40 large T antigen-induced primitive neuroectodermal tumor cell lines of the rat. , 1999, Carcinogenesis.

[39]  Kamel Khalili,et al.  Human ubiquitous JCV(CY) T-antigen gene induces brain tumors in experimental animals , 1999, Oncogene.

[40]  V. Rusch,et al.  A multi-institutional study confirms the presence and expression of simian virus 40 in human malignant mesotheliomas. , 1998, Cancer research.

[41]  C. Raffel,et al.  Sporadic Medulloblastomas Contain Oncogenic β-Catenin Mutations , 1998 .

[42]  F. Behm,et al.  Extensive genomic abnormalities in childhood medulloblastoma by comparative genomic hybridization. , 1997, Cancer research.

[43]  R. Baserga,et al.  Co-operation of Simian virus 40 T antigen and insulin receptor substrate-1 in protection from apoptosis induced by Interleukin-3 withdrawal , 1997, Oncogene.

[44]  T. Ludwig,et al.  Mouse mutants lacking the type 2 IGF receptor (IGF2R) are rescued from perinatal lethality in Igf2 and Igf1r null backgrounds. , 1996, Developmental biology.

[45]  F. Grummt,et al.  p53 inhibits JC virus DNA replication in vivo and interacts with JC virus large T-antigen. , 1996, Virology.

[46]  Carissa A. Sanchez,et al.  Inactivation of p53 and the Development of Tetraploidy in the Elastase‐SV40 T Antigen Transgenic Mouse Pancreas , 1995, Pancreas.

[47]  R. Baserga,et al.  Association of insulin receptor substrate 1 with simian virus 40 large T antigen , 1995, Molecular and cellular biology.

[48]  A. Aguzzi,et al.  Deregulated expression of PAX5 in medulloblastoma. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[49]  S. Bacchetti,et al.  Induction of genomic instability in SV40 transformed human cells: sufficiency of the N-terminal 147 amino acids of large T antigen and role of pRB and p53. , 1994, Oncogene.

[50]  E. Gurney,et al.  The genomic instability associated with integrated simian virus 40 DNA is dependent on the origin of replication and early control region , 1994, Journal of virology.

[51]  R. Garcea,et al.  DNA sequences similar to those of simian virus 40 in ependymomas and choroid plexus tumors of childhood. , 1992, The New England journal of medicine.

[52]  G. Basso,et al.  N-MYC and C-MYC Oncogenes Amplification in Medulloblastomas. Evidence of Particularly Aggressive Behavior of a Tumor with C-MYC Amplification , 1991, Tumori.

[53]  G. Khoury,et al.  The early region of human papovavirus JC induces dysmyelination in transgenic mice , 1986, Cell.

[54]  S. Ohsumi,et al.  INDUCTION OF UNDIFFERENTIATED TUMORS BY JC VIRUS IN THE CEREBRUM OF RATS , 1986, Acta pathologica japonica.

[55]  J. Krischer,et al.  Cisplatin in recurrent pediatric brain tumors A pog phase II study a pediatric oncology group study , 1985, Cancer.

[56]  E. Major,et al.  JC virus-induced owl monkey glioblastoma cells in culture: biological properties associated with the viral early gene product. , 1984, Virology.

[57]  G. Blandino,et al.  [Metastases of the sub-arachnoidal space from medulloblastoma. Computed tomography study]. , 1982, Journal de radiologie.

[58]  Z. Gm,et al.  Perinatal induction of medulloblastomas in Syrian golden hamsters by a human polyoma virus (JC). , 1979 .

[59]  B. Padgett,et al.  Human Papovavirus (JC): Induction of Brain Tumors in Hamsters , 1973, Science.

[60]  A. Donfrancesco,et al.  High-dose carboplatin in combination with etoposide (JET regimen) for childhood brain tumors. , 1990, The American journal of pediatric hematology/oncology.

[61]  J. Allen,et al.  Cisplatin in the treatment of recurrent childhood primary brain tumors. , 1988, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[62]  D. Bigner,et al.  Structural chromosomal abnormalities in human medulloblastoma. , 1988, Cancer genetics and cytogenetics.

[63]  P. Mckeever,et al.  Viral-induced astrocytomas in squirrel monkeys. , 1983, Progress in clinical and biological research.

[64]  J. Varakis,et al.  Perinatal induction of medulloblastomas in Syrian golden hamsters by a human polyoma virus (JC). , 1979, National Cancer Institute monograph.