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Trans-repressive effect of NUP98-PMX1 on PMX1-regulated c-FOS gene through recruitment of histone deacetylase 1 by FG repeats.

Abstract
The formation of fusion genes between NUP98 and members of the HOX family represents a critical factor for the genesis of acute leukemia or acute transformation of chronic myeloid leukemia (CML). To gain insights into the molecular mechanisms underlying the leukemogenesis of NUP98-HOX fusion products, we cloned NUP98-PMX1 from a CML-blast crisis patient with t(1;11) as a secondary chromosomal translocation, and functionally studied the fusion products in detail through various molecular and protein biochemical assays. In addition to many interesting features, we have found that the NUP98-PMX1 fusion protein exerts a repressive effect on PMX1 or serum response factor-mediated c-FOS activation, probably through the recruitment of a common corepressor histone deacetylase 1 by FG domains of the NUP98-PMX1 fusion protein. Moreover, we have provided evidence that the FG domains of NUP98-PMX1 and two other NUP98-containing fusion proteins, i.e., NUP98-HOXA9 and NUP98-HOXC11, all exhibit dual binding ability to both CREB binding protein, a coactivator, and histone deacetylase 1, a corepressor. Accordingly, we have hypothesized that this dual binding activity is shared by most, if not all, NUP98-HOX-involved fusion proteins, enabling these fusion proteins to act as both trans-activators and trans-repressors, and contributing to the genesis of acute leukemia or acute transformation of CML.
AuthorsXue-Tao Bai, Bai-Wei Gu, Tong Yin, Chao Niu, Xiao-Dong Xi, Ji Zhang, Zhu Chen, Sai-Juan Chen
JournalCancer research (Cancer Res) Vol. 66 Issue 9 Pg. 4584-90 (May 01 2006) ISSN: 0008-5472 [Print] United States
PMID16651408 (Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • NUP98-PMX1 fusion protein, human
  • Nuclear Pore Complex Proteins
  • Oncogene Proteins, Fusion
  • HDAC1 protein, human
  • Histone Deacetylase 1
  • Histone Deacetylases
Topics
  • Binding Sites
  • Blast Crisis
  • Cell Nucleus (genetics, metabolism)
  • Cloning, Molecular
  • Gene Expression Regulation, Leukemic
  • Genes, fos
  • Histone Deacetylase 1
  • Histone Deacetylases (metabolism)
  • Humans
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive (genetics, metabolism, pathology)
  • Male
  • Middle Aged
  • Nuclear Pore Complex Proteins (genetics, metabolism)
  • Oncogene Proteins, Fusion (genetics, metabolism)
  • Protein Structure, Tertiary
  • Transcriptional Activation

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