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PU.1 inhibits GATA-1 function and erythroid differentiation by blocking GATA-1 DNA binding

Academic Article
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Overview

authors

  • Zhang, P.
  • Zhang, X. B.
  • Iwama, A.
  • Yu, C. N.
  • Smith, K. A.
  • Mueller, B. U.
  • Narravula, S.
  • Torbett, Bruce
  • Orkin, S. H.
  • Tenen, D. G.

publication date

  • October 2000

journal

  • Blood  Journal

abstract

  • The lineage-specific transcription factors GATA-1 and PU.1 can physically interact to inhibit each other's function, but the mechanism of repression of GATA-1 function by PU.1 has not been elucidated. Both the N terminus and the C terminus of PU.1 can physically interact with the C-terminal zinc finger of GATA-1. It is demonstrated that the PU.1 N terminus, but not the C terminus, is required for inhibiting GATA-1 function. Induced overexpression of PU.1 in K562 erythroleukemia cells blocks hemin-induced erythroid differentiation. In this system, PU.1 does not affect the expression of GATA-1 messenger RNA, protein, or nuclear localization. However, GATA-1 DNA binding decreases dramatically. By means of electrophoretic mobility shift assays with purified proteins, it is demonstrated that the N-terminal 70 amino acids of PU.1 can specifically block GATA-1 DNA binding. In addition, PU.1 had a similar effect in the G1ER cell line, in which the GATA-1 null erythroid cell line G1E has been transduced with a GATA-1-estrogen receptor fusion gene, which is directly dependent on induction of the GATA-1 fusion protein to effect erythroid maturation. Consistent with in vitro binding assays, overexpression of PU.1 blocked DNA binding of the GATA-1 fusion protein as well as GATA-1-mediated erythroid differentiation of these G1ER cells. These results demonstrate a novel mechanism by which function of a lineage-specific transcription factor is inhibited by another lineage-restricted factor through direct protein-protein interactions. These findings contribute to understanding how protein-protein interactions participate in hematopoietic differentiation and leukemogenesis. (Blood. 2000;96:2641-2648)

subject areas

  • Biological Transport
  • Cell Differentiation
  • Cell Lineage
  • Cell Nucleus
  • DNA
  • DNA, Neoplasm
  • DNA-Binding Proteins
  • Erythroid Precursor Cells
  • Erythroid-Specific DNA-Binding Factors
  • Erythropoiesis
  • Estradiol
  • GATA1 Transcription Factor
  • Gene Expression Regulation, Leukemic
  • Genes, Synthetic
  • Humans
  • K562 Cells
  • Neoplasm Proteins
  • Protein Binding
  • Protein Structure, Tertiary
  • Proto-Oncogene Proteins
  • RNA, Messenger
  • RNA, Neoplasm
  • Receptors, Estrogen
  • Recombinant Fusion Proteins
  • Trans-Activators
  • Transcription Factors
  • Transfection
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Identity

International Standard Serial Number (ISSN)

  • 0006-4971

PubMed ID

  • 11023493
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Additional Document Info

start page

  • 2641

end page

  • 2648

volume

  • 96

issue

  • 8

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