Pivotal role for the NFIL3/E4BP4 transcription factor in interleukin 3-mediated survival of pro-B lymphocytes.
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.
Ikushima
S
S
Department of Experimental Oncology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Inukai
T
T
Inaba
T
T
Nimer
S D
SD
Cleveland
J L
JL
Look
A T
AT
D017504:Adenovirus E4 Proteins / Q000235:genetics; D000818:Animals; D017209:Apoptosis; D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D001483:Base Sequence; D050976:Basic-Leucine Zipper Transcription Factors; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000378:metabolism*; D051790:G-Box Binding Factors; D006801:Humans; D007377:Interleukin-3 / Q000494:pharmacology*; D016350:Leucine Zippers; D051379:Mice; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000378:metabolism; D014157:Transcription Factors / Q000096:biosynthesis / Q000378:metabolism*; D014162:Transfection
D017504:Adenovirus E4 Proteins; D050976:Basic-Leucine Zipper Transcription Factors; D004268:DNA-Binding Proteins; D051790:G-Box Binding Factors; C490671:HLF protein, human; C490670:Hlf protein, mouse; D007377:Interleukin-3; C497440:NFIL3 protein, human; C497441:Nfil3 protein, mouse; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors