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The proto-oncogene HLF and the related basic leucine zipper protein TEF
display highly similar DNA-binding and transcriptional regulatory
properties
SP Hunger, S Li, MZ Fall, L Naumovski and ML Cleary
Section of Pediatric Hematology/Oncology, Department of Pediatrics,
University of Colorado School of Medicine, Denver, CO, USA.
Genes encoding transcription factors are frequently altered by chromosomal
translocations in acute lymphoblastic leukemia (ALL), suggesting that
aberrant transcriptional regulation plays a prominent role in
leukemogenesis. E2A-hepatic leukemia factor (HLF), a chimeric transcription
factor created by the t(17;19), consists of the amino terminal portion of
E2A proteins, including two experimentally defined transcriptional
activation domains (TADs), fused to the HLF DNA binding and protein
dimerization basic leucine zipper (bZIP) domain. To understand the
mechanisms by which E2A-HLF induces leukemia and the crucial functions
contributed by each constituent of the chimera, it is essential to define
the normal transcriptional regulatory properties of HLF and related bZIP
proteins. To address these questions, we cloned the human homologue of
TEF/VBP, a bZIP protein closely related to HLF. Using a binding site
selection assay, we found that TEF bound preferentially to the consensus
sequence 5'-GTTACGTAAT-3', which is identical to the previously determined
HLF recognition site. TEF and HLF activated transcription of consensus
site-containing reporter genes in several different cell types with similar
potencies. Using GAL4 chimeric proteins, a TAD was mapped to a discrete
approximate 40 amino acid region of TEF and HLF within which they share 72%
amino acid identity and 85% similarity. The TEF/HLF activation domain
(THAD) has a predicted helical secondary structure, but shares no sequence
homology with previously reported TADs. The THAD contained most, if not
all, of the transcriptional activation properties present in both TEF and
HLF and its deletion completely abrogated transcriptional activity of TEF
and HLF in both mammalian cells and yeast. Thus, TEF and HLF share
indistinguishable DNA-binding and transcriptional regulatory properties,
whose alteration in leukemia may be pathogenetically important.
Volume 87,
Issue 11,
pp. 4607-4617,
06/01/1996
Copyright © 1996 by The American Society of Hematology
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