title: N-Myc differentially regulates expression of MXI1 isoforms in neuroblastoma.
abstract: Amplification of the MYCN proto-oncogene is associated with a poor prognosis in patients with metastatic neuroblastoma (NB). MYCN encodes the N-Myc protein, a transcriptional regulator that dimerizes with the Max transcription factor, binds to E-box DNA sequences, and regulates genes involved in cell growth and apoptosis. Overexpression of N-Myc leads to transcriptional activation and an increase in NB cell proliferation. Mxi1, a member of the Myc family of transcriptional regulators, also binds to Max. However, Mxi1 is a transcriptional repressor and inhibits proliferation of NB cells, suggesting that Mxi1 functions as an N-Myc antagonist. Our laboratory previously identified Mxi1-0, an alternatively transcribed Mxi1 isoform. Mxi1-0 has properties distinct from those of Mxi1; in contrast to Mxi1, Mxi1-0 is unable to suppress c-Myc-dependent transcription. We now show that Mxi1-0 expression increases in response to MYCN overexpression in NB cells, with a positive correlation between MYCN and MXI1-0 RNA levels. We also show that N-Myc expression differentially regulates the MXI1 and MXI1-0 promoters: Increased MYCN expression suppresses MXI1 promoter activity while enhancing transcription through the MXI1-0 promoter. Finally, induction of Mxi1-0 leads to increased proliferation, whereas expression of Mxi1 inhibits cell growth, indicating differential roles for these two proteins. These data suggest that N-Myc differentially regulates the expression of MXI1 and MXI1-0 and can alter the balance between the two transcription factors. Furthermore, MXI1-0 appears to be a downstream target of MYCN-dependent signaling pathways and may contribute to N-Myc-dependent cell growth and proliferation.
authors.affiliation: Division 1of Pediatric Hematology-Oncology, Department of Pediatrics, Duke University Medical Center, Durham, NC.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Armstrong
authors.affiliation: Section of Pediatric Hematology-Oncology, Department of Pediatrics and Communicable Diseases, University of Michigan School of Medicine, Ann Arbor, MI.
authors.forename: Rajen J
authors.initials: RJ
authors.lastname: Mody
authors.affiliation: Division 1of Pediatric Hematology-Oncology, Department of Pediatrics, Duke University Medical Center, Durham, NC.
authors.forename: D Christian
authors.initials: DC
authors.lastname: Ellis
authors.affiliation: Division 1of Pediatric Hematology-Oncology, Department of Pediatrics, Duke University Medical Center, Durham, NC.
authors.forename: Adam B
authors.initials: AB
authors.lastname: Hill
authors.affiliation: Section of Pediatric Hematology-Oncology, Department of Pediatrics and Communicable Diseases, University of Michigan School of Medicine, Ann Arbor, MI.
authors.forename: David A
authors.initials: DA
authors.lastname: Erichsen
authors.affiliation: Division 1of Pediatric Hematology-Oncology, Department of Pediatrics, Duke University Medical Center, Durham, NC ; Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Wechsler
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005784:Gene Amplification; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000071447:N-Myc Proto-Oncogene Protein; D009447:Neuroblastoma; D009687:Nuclear Proteins / Q000502:physiology*; D015513:Oncogene Proteins / Q000502:physiology*; D011401:Promoter Regions, Genetic; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D000090063:Proto-Oncogene Mas; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D020033:Protein Isoforms; D000090063:Proto-Oncogene Mas; D012333:RNA, Messenger; D025521:Tumor Suppressor Proteins; C000715470:MAS1 protein, human; C079440:MXI1 protein, human; C459801:MYCN protein, human