Role for E2F1 in p210 BCR-ABL downstream regulation of c-myc transcription initiation. Studies in murine myeloid cells

M. J. Stewart, S. Litz-Jackson, G. S. Burgess, E. A. Williamson, D. S. Leibowitz, H. S. Boswell

Research output: Contribution to journalArticle

40 Scopus citations

Abstract

Experiments were performed to elucidate the mechanism through which p210 BCR-ABL, by its downstream signals, regulates c-myc messenger RNA expression in hematopoietic cells. We studied a model system in which stable expression of p210 BCR-ABL in interleukin-3 (IL-3) dependent murine myeloid cell lines led to growth factor independent transformation. Active c-myc transcription was observed in p210 BCR-ABL transformed cells by nuclear run-on assay, and in heterologous reporter assays performed with the 5' regulatory region of murine c-myc linked to firefly luciferase. Transcription initiation occurred primarily from the P2 promoter in p210 BCR-ABL transformed cells. Cis and trans elements responsible for transcription initiation from the c-myc P2 promoter were studied. Expression of E2F1 protein in p210 BCR-ABL transformed cells accounted, in part, for binding to the E2F site of the P2 c-myc promoter. The functional importance of E2F1 expression in p210 BCR-ABL transformed cells toward c-myc transcription was established in reporter assays performed with the P2 c-myc promoter containing either wild-type or mutant E2F sites. Mutation of the E2F motif of P2 5' c-myc reduced activity of the promoter by 50%. By gel mobility shift, E2F1 was found in P2 c-myc band shift complexes along with the cyclin-dependent kinase 2. Therefore, coupling of E2F to components of the retinoblastoma-cyclin pathway defines a route from p210 BCR-ABL to, c-myc transcription, which is required for p210 BCR-ABL transformation.

Original languageEnglish (US)
Pages (from-to)1499-1507
Number of pages9
JournalLeukemia
Volume9
Issue number9
StatePublished - Sep 1995

Keywords

  • BCR-ABL
  • E2F1
  • c-myc

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

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    Stewart, M. J., Litz-Jackson, S., Burgess, G. S., Williamson, E. A., Leibowitz, D. S., & Boswell, H. S. (1995). Role for E2F1 in p210 BCR-ABL downstream regulation of c-myc transcription initiation. Studies in murine myeloid cells. Leukemia, 9(9), 1499-1507.