Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 278, Issue 5, Pages 2983-2989Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M207596200
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Amplification of the MYCN gene, resulting in overexpression. of MYCN, distinguishes a subset of neuroblastomas with poor prognosis. The transcription factors driving MYCN expression in neuroblastomas are unknown. In transient-transfection assays, E2F-1, E2F-2, and E2F-3 activate a MYCN reporter construct dependent on the presence of several putative E2F-binding sites. Using chromatin immunoprecipitation, we show that E2F-1, E2F-2, and E2F-3 bind to the proximal MYCN promoter in vivo, specifically in neuroblastoma cell lines expressing MYCN. Inhibition of E2F activity in MYCN-amplified cells by the overexpression of p16(INK4A) reduced MYCN expression. In addition, we provide evidence that E2F proteins are involved in the negative regulation of MYCN by TGF-beta and retinoic acid. These data suggest that E2F transcription factors are critical for both the full activation and the repression of MYCN in neuroblastomas.
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