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

• Published in: Cancer research (Chicago, Ill.) Ill.), 2006-05, Vol.66 (9), p.4584-4590
• Main Authors: BAI, Xue-Tao, GU, Bai-Wei, TONG YIN, CHAO NIU, XI, Xiao-Dong, JI ZHANG, ZHU CHEN, CHEN, Sai-Juan
• Format: Article
• Language: English
• Subjects: Antineoplastic agents; Binding Sites; Biological and medical sciences; Blast Crisis; Cell Nucleus - genetics; Cell Nucleus - metabolism; Cloning, Molecular; Gene Expression Regulation, Leukemic; Genes, fos; Histone Deacetylase 1; Histone Deacetylases - metabolism; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - genetics; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - metabolism; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - pathology; Male; Medical sciences; Middle Aged; Nuclear Pore Complex Proteins - genetics; Nuclear Pore Complex Proteins - metabolism; Oncogene Proteins, Fusion - genetics; Oncogene Proteins, Fusion - metabolism; Pharmacology. Drug treatments; Protein Structure, Tertiary; Transcriptional Activation; Tumors
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-05-3101

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.