Pivotal role for the NFIL3/E4BP4 transcription factor in interleukin 3- mediated survival of pro-B lymphocytes

S. Ikushima, T. Inukai, T. Inaba, Stephen D Nimer, J. L. Cleveland, A. T. Look

Research output: Contribution to journalArticle

110 Citations (Scopus)

Abstract

The E2A-HLF (hepatic leukemia factor) oncoprotein, generated in pro-B lymphocytes by fusion of the trans-activation domain of E2A to the basic region/leucine zipper (bZIP) domain of HLF, functions as an anti-apoptotic transcription factor in leukemic cell transformation. When introduced into interleukin 3 (IL-3)-dependent mouse pro-B lymphocytes, E2A-HLF prevents apoptosis induced by growth factor deprivation, suggesting that IL-3 mediates cell survival through activation of a transcription factor whose activity can be constitutively replaced by the chimeric oncoprotein. We considered four bZIP transcription factors as candidates for this putative IL-3-regulated factor, each of which binds avidly to the DNA consensus sequence recognized by E2A-HLF and is related to the Caenorhabditis elegans CES-2 (cell death specification protein) neuron-specific mediator of cell death. The expression and binding activity of the Nfil3 protein (also called E4bp4), but not of Hlf, Dbp, or Tef, was found to be regulated by IL-3 in mouse pro-B cell lines (Baf-3 and FL5.12). Northern blot analysis showed that Nfil3/E4bp4 is regulated as a 'delayed-early' IL-3-responsive gene, requiring de novo protein synthesis. In the absence of IL-3, enforced expression of the human NFIL3/E4BP4 cDNA promoted the survival but not the growth of IL-3-dependent pro-B cells. Our results implicate NFIL3/E4BP4 (nuclear factor regulated by IL-3/adenovirus E4 promoter binding protein) in a distinct growth factor- regulated signaling pathway that is responsible for the survival of early B- cell progenitors, and whose alteration by E2A-HLF leads to childhood B lineage leukemia.

Original languageEnglish
Pages (from-to)2609-2614
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume94
Issue number6
DOIs
StatePublished - Apr 8 1997
Externally publishedYes

Fingerprint

B-Lymphoid Precursor Cells
Interleukin-3
Transcription Factors
Oncogene Proteins
Intercellular Signaling Peptides and Proteins
Leukemia
Cell Death
Basic-Leucine Zipper Transcription Factors
Leucine Zippers
Proteins
Consensus Sequence
Caenorhabditis elegans
Adenoviridae
Northern Blotting
Cell Survival
Carrier Proteins
Complementary DNA
Apoptosis
Neurons
Cell Line

Keywords

  • apoptosis
  • hematopoietic growth factor
  • leukemia
  • signal transduction

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Pivotal role for the NFIL3/E4BP4 transcription factor in interleukin 3- mediated survival of pro-B lymphocytes. / Ikushima, S.; Inukai, T.; Inaba, T.; Nimer, Stephen D; Cleveland, J. L.; Look, A. T.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 94, No. 6, 08.04.1997, p. 2609-2614.

Research output: Contribution to journalArticle

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