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N-Myc Differentially Regulates Expression of MXI1 Isoforms in Neuroblastoma
- Source :
- Neoplasia: An International Journal for Oncology Research, Vol 15, Iss 12, Pp 1363-1370 (2013)
- Publication Year :
- 2013
- Publisher :
- Elsevier, 2013.
-
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.
- Subjects :
- Neoplasms. Tumors. Oncology. Including cancer and carcinogens
RC254-282
Subjects
Details
- Language :
- English
- ISSN :
- 14765586 and 15228002
- Volume :
- 15
- Issue :
- 12
- Database :
- Directory of Open Access Journals
- Journal :
- Neoplasia: An International Journal for Oncology Research
- Publication Type :
- Academic Journal
- Accession number :
- edsdoj.21774cfcdc4a45ab9cebbd3691946a51
- Document Type :
- article
- Full Text :
- https://doi.org/10.1593/neo.11606