BIN1 inhibits colony formation and induces apoptosis in neuroblastoma cell lines with MYCN amplification.

BACKGROUND MYCN amplification and overexpression occurs in 25% of neuroblastomas and independently predicts for poor prognosis disease, an effect thought to be mediated by its role as a transcriptional activator of growth promoting genes. However, in many mammalian cells, deregulated expression of MYC family genes (including MYCN) induces apoptosis. We hypothesized that BIN1, a MYC interacting protein capable of inducing apoptosis, may be an important regulator of MYCN in neuroblastoma. RESULTS BIN1 expression was found to be reduced in MYCN-amplified cell lines. Further, forced expression of BIN1 markedly reduced colony formation in MYCN-amplified, but not single-copy, cell lines. This effect appeared to be caused by an increase in apoptosis, and was augmented by serum deprivation and concurrent cytotoxic drug therapy in cell culture CONCLUSION BIN1 inactivation may be necessary for MYCN overexpression to lead to cellular proliferation rather than programmed cell death in neuroblastomas with MYCN amplification.

[1]  R. Hofstra,et al.  GFR alpha-3 variants in human lung carcinoma. , 2000 .

[2]  F. Behm,et al.  Caspase 8 is deleted or silenced preferentially in childhood neuroblastomas with amplification of MYCN , 2000, Nature Medicine.

[3]  Wei Du,et al.  Bin1 functionally interacts with Myc and inhibits cell proliferation via multiple mechanisms , 1999, Oncogene.

[4]  G. Prendergast,et al.  Mechanisms of apoptosis by c-Myc , 1999, Oncogene.

[5]  M. Schwab,et al.  MycN sensitizes neuroblastoma cells for drug-induced apoptosis , 1999, Oncogene.

[6]  M. Schwab,et al.  MycN and IFNγ cooperate in apoptosis of human neuroblastoma cells , 1998, Oncogene.

[7]  M. Herlyn,et al.  The putative tumor suppressor BIN1 is a short-lived nuclear phosphoprotein, the localization of which is altered in malignant cells. , 1997, Cancer research.

[8]  R. Eisenman,et al.  Myc target genes. , 1997, Trends in biochemical sciences.

[9]  Robert Wechsler-Reya,et al.  BIN1 is a novel MYC–interacting protein with features of a tumour suppressor , 1996, Nature Genetics.

[10]  D. Green,et al.  Apoptotic cell death induced by c-myc is inhibited by bcl-2 , 1992, Nature.

[11]  Gerard I. Evan,et al.  Induction of apoptosis in fibroblasts by c-myc protein , 1992, Cell.

[12]  H. Sather,et al.  Association of multiple copies of the N-myc oncogene with rapid progression of neuroblastomas. , 1985, The New England journal of medicine.

[13]  H. Varmus,et al.  Amplification of N-myc in untreated human neuroblastomas correlates with advanced disease stage. , 1984, Science.