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Molecular and Cellular Biology, October 1998, p. 6035-6043, Vol. 18, No. 10
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

The AD1 and AD2 Transactivation Domains of E2A Are Essential for the Antiapoptotic Activity of the Chimeric Oncoprotein E2A-HLF

Takeshi Inukai,1,dagger Toshiya Inaba,2 Satoshi Ikushima,1,Dagger and A. Thomas Look1,3,*

Department of Experimental Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee 381051; Department of Molecular Biology, Jichi Medical School, Tochigi 329-04, Japan2; and Department of Pediatrics, University of Tennessee College of Medicine, Memphis, Tennessee 381633

Received 27 May 1998/Accepted 1 July 1998

The chimeric oncoprotein E2A-HLF, generated by the t(17;19) chromosomal translocation in pro-B-cell acute lymphoblastic leukemia, incorporates the transactivation domains of E2A and the basic leucine zipper (bZIP) DNA-binding and protein dimerization domain of HLF (hepatic leukemic factor). The ability of E2A-HLF to prolong the survival of interleukin-3 (IL-3)-dependent murine pro-B cells after IL-3 withdrawal suggests that it disrupts signaling pathways normally responsible for cell suicide, allowing the cells to accumulate as transformed lymphoblasts. To determine the structural motifs that contribute to this antiapoptotic effect, we constructed a panel of E2A-HLF mutants and programmed their expression in IL-3-dependent murine pro-B cells (FL5.12 line), using a zinc-inducible vector. Neither the E12 nor the E47 product of the E2A gene nor the wild-type HLF protein was able to protect the cells from apoptosis induced by IL-3 deprivation. Surprisingly, different combinations of disabling mutations within the HLF bZIP domain had little effect on the antiapoptotic property of the chimeric protein, so long as the amino-terminal portion of E2A remained intact. In the context of a bZIP domain defective in DNA binding, mutants retaining either of the two transactivation domains of E2A were able to extend cell survival after growth factor deprivation. Thus, the block of apoptosis imposed by E2A-HLF in pro-B lymphocytes depends critically on the transactivating regions of E2A. Since neither DNA binding nor protein dimerization through the bZIP domain of HLF is required for this effect, we propose mechanisms whereby protein-protein interactions with the amino-terminal region of E2A allow the chimera to act as a transcriptional cofactor to alter the expression of genes regulating the apoptotic machinery in pro-B cells.

* Corresponding author. Mailing address: Department of Experimental Oncology, St. Jude Children's Research Hospital, 332 N. Lauderdale, Memphis, TN 38105. Phone: (901) 495-3514. Fax: (901) 495-2032. E-mail: thomas.look{at}stjude.org.

dagger Present address: Department of Pediatrics, Yamanashi Medical University, Tamaho, Yamanashi 409-38, Japan.

Dagger Present address: Department of Pediatrics, Kyoto Prefectural University of Medicine, Sakyo-ku, Kyoto 602, Japan.

Molecular and Cellular Biology, October 1998, p. 6035-6043, Vol. 18, No. 10
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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