Three distinct domains in TEL-AML1 are required for transcriptional repression of the IL-3 promoter

Hideo Uchida, James R. Downing, Yasushi Miyazaki, Richard Frank, Jin Zhang, Stephen D Nimer

Research output: Contribution to journalArticle

48 Citations (Scopus)

Abstract

A cytogenetically cryptic (12;21) translocation is the most common molecular abnormality identified in childhood acute lymphoblastic leukemia (ALL), and it generates a chimeric TEL-AML1 protein. Fusion of the Helix-Loop-Helix (HLH) (also called the pointed) domain of TEL to AML1 has been suggested to convert AML1 from a transcriptional activator to a repressor. To define the structural features of this chimeric protein required for repression, we analysed the transcriptional activity of a series of TEL-AML1 mutants on the AML1-responsive interleukin-3 (IL-3) promoter, a potentially relevant gene target. Our results demonstrate that TEL-AML1 represses basal IL-3 promoter activity in lymphoid cells, and deletion mutant analysis identified three distinct domains of TEL-AML1 that are required for repression; the HLH (pointed) motif contained in the TEL portion of TEL-AML1, and both the homology domain (Rhd) and the 74 amino downstream of the Rhd that are present in the AML1 portion of the fusion protein. Although AML1B (and a shorter AML1 isoform, AML1A) have transcriptional activating activity on the IL-3 promoter, fusion of the AML1 gene to the TEL gene generates a repressor of IL-3 expression. Consistent with this activity, freshly isolated human ALL cells that contain TEL-AML1 do not express IL-3.

Original languageEnglish
Pages (from-to)1015-1022
Number of pages8
JournalOncogene
Volume18
Issue number4
DOIs
StatePublished - Jan 28 1999
Externally publishedYes

Fingerprint

Interleukin-3
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Helix-Loop-Helix Motifs
Gene Fusion
Genes
Protein Isoforms
Proteins
Lymphocytes

Keywords

  • Repression
  • TEL-AML1
  • Transcription

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Three distinct domains in TEL-AML1 are required for transcriptional repression of the IL-3 promoter. / Uchida, Hideo; Downing, James R.; Miyazaki, Yasushi; Frank, Richard; Zhang, Jin; Nimer, Stephen D.

In: Oncogene, Vol. 18, No. 4, 28.01.1999, p. 1015-1022.

Research output: Contribution to journalArticle

Uchida, Hideo ; Downing, James R. ; Miyazaki, Yasushi ; Frank, Richard ; Zhang, Jin ; Nimer, Stephen D. / Three distinct domains in TEL-AML1 are required for transcriptional repression of the IL-3 promoter. In: Oncogene. 1999 ; Vol. 18, No. 4. pp. 1015-1022.
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