TEF, an antiapoptotic bZIP transcription factor related to the oncogenic E2A-HLF chimera, inhibits cell growth by down-regulating expression of the common beta chain of cytokine receptors.
Gain and/or loss of function mediated by chimeric transcription factors generated by nonrandom translocations in leukemia is a key to understanding oncogenesis. E2A-hepatic leukemia factor (HLF), a chimeric basic region/leucine zipper (bZIP) transcription factor expressed in t(17;19)-positive leukemia cells, contributes to leukemogenesis through its potential to inhibit apoptosis. To identify physiologic counterparts of this chimera, we investigated the function of other bZIP factors that bind to the same DNA sequence recognized by E2A-HLF. Here, we show that thyrotroph embryonic factor (TEF), which shares a high level of sequence identity with HLF and recognizes the same DNA sequence, is expressed in a small fraction of each subset of hematolymphoid progenitors. When TEF was introduced into FL5.12 interleukin 3 (IL-3)-dependent cells, TEF protected the cells from apoptosis due to IL-3 deprivation. Unexpectedly, TEF also almost completely down-regulated expression of the common beta (betac) chain of cytokine receptors. Consequently, TEF-expressing cells accumulated in G(0)/G(1) phase without undergoing apoptosis. These findings suggest that TEF is one of the apoptotic regulators in hematopoietic progenitors and controls hematopoietic-cell proliferation by regulating the expression of the betac chain. In contrast, E2A-HLF promoted cell survival more efficiently than TEF but did not down-regulate betac chain expression, suggesting that E2A-HLF retains ideal properties for driving leukemic transformation.
Inukai
Takeshi
T
Department of Pediatrics, School of Medicine, University of Yamanashi, 1110 Shimokato, Tamaho-cho, Nakakoma-gun, Yamanashi 409-3898, Japan. tinukai@yamanashi.ac.jp
Inaba
Toshiya
T
Dang
Jinjun
J
Kuribara
Ryoko
R
Ozawa
Keiya
K
Miyajima
Atsushi
A
Wu
Wenshu
W
Look
A Thomas
AT
Arinobu
Yojiro
Y
Iwasaki
Hiromi
H
Akashi
Koichi
K
Kagami
Keiko
K
Goi
Kumiko
K
Sugita
Kanji
K
Nakazawa
Shinpei
S
D000818:Animals; D017209:Apoptosis; D050976:Basic-Leucine Zipper Transcription Factors; D002460:Cell Line; D049109:Cell Proliferation; D053648:Cytokine Receptor Common beta Subunit; D004268:DNA-Binding Proteins / Q000235:genetics / Q000494:pharmacology; D015536:Down-Regulation; D005786:Gene Expression Regulation; D006412:Hematopoietic Stem Cells / Q000166:cytology; D007377:Interleukin-3 / Q000494:pharmacology; D051379:Mice; D009154:Mutation; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000235:genetics; D018121:Receptors, Cytokine / Q000235:genetics*; D016192:Resting Phase, Cell Cycle; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D014161:Transduction, Genetic
D050976:Basic-Leucine Zipper Transcription Factors; C115876:CSF2RB protein, human; D053648:Cytokine Receptor Common beta Subunit; D004268:DNA-Binding Proteins; C076554:E2a-Hlf fusion protein, human; D007377:Interleukin-3; D015514:Oncogene Proteins, Fusion; D011956:Receptors, Cell Surface; D018121:Receptors, Cytokine; C489490:TEF protein, human; D014157:Transcription Factors