• Register
X
Forgot Password

If you have forgotten your password you can enter your email here and get a temporary password sent to your email.

X

Leaving Community

Are you sure you want to leave this community? Leaving the community will revoke any permissions you have been granted in this community.

No
Yes

ETO, a target of t(8;21) in acute leukemia, makes distinct contacts with multiple histone deacetylases and binds mSin3A through its oligomerization domain.

t(8;21) and t(16;21) create two fusion proteins, AML-1-ETO and AML-1-MTG16, respectively, which fuse the AML-1 DNA binding domain to putative transcriptional corepressors, ETO and MTG16. Here, we show that distinct domains of ETO contact the mSin3A and N-CoR corepressors and define two binding sites within ETO for each of these corepressors. In addition, of eight histone deacetylases (HDACs) tested, only the class I HDACs HDAC-1, HDAC-2, and HDAC-3 bind ETO. However, these HDACs bind ETO through different domains. We also show that the murine homologue of MTG16, ETO-2, is also a transcriptional corepressor that works through a similar but distinct mechanism. Like ETO, ETO-2 interacts with N-CoR, but ETO-2 fails to bind mSin3A. Furthermore, ETO-2 binds HDAC-1, HDAC-2, and HDAC-3 but also interacts with HDAC-6 and HDAC-8. In addition, we show that expression of AML-1-ETO causes disruption of the cell cycle in the G(1) phase. Disruption of the cell cycle required the ability of AML-1-ETO to repress transcription because a mutant of AML-1-ETO, Delta469, which removes the majority of the corepressor binding sites, had no phenotype. Moreover, treatment of AML-1-ETO-expressing cells with trichostatin A, an HDAC inhibitor, restored cell cycle control. Thus, AML-1-ETO makes distinct contacts with multiple HDACs and an HDAC inhibitor biologically inactivates this fusion protein.

Pubmed ID: 11533236

Authors

  • Amann JM
  • Nip J
  • Strom DK
  • Lutterbach B
  • Harada H
  • Lenny N
  • Downing JR
  • Meyers S
  • Hiebert SW

Journal

Molecular and cellular biology

Publication Data

October 4, 2001

Associated Grants

  • Agency: NCI NIH HHS, Id: CA68485
  • Agency: NCI NIH HHS, Id: P01 CA71907
  • Agency: NIA NIH HHS, Id: R01-AG13726
  • Agency: NCI NIH HHS, Id: R01-CA64140
  • Agency: NCI NIH HHS, Id: R01-CA76186
  • Agency: NCI NIH HHS, Id: R01-CA77274

Mesh Terms

  • Amino Acid Sequence
  • Animals
  • Binding Sites
  • Cell Line
  • Core Binding Factor Alpha 2 Subunit
  • DNA-Binding Proteins
  • Enzyme Inhibitors
  • Histone Deacetylase Inhibitors
  • Histone Deacetylases
  • Hydroxamic Acids
  • Leukemia, Myelomonocytic, Acute
  • Mice
  • Models, Genetic
  • Molecular Sequence Data
  • Nuclear Proteins
  • Nuclear Receptor Co-Repressor 1
  • Oncogene Proteins, Fusion
  • Protein Structure, Tertiary
  • Proto-Oncogene Proteins
  • Repressor Proteins
  • Sequence Homology, Amino Acid
  • Transcription Factors
  • Transcription, Genetic
  • Translocation, Genetic