Hu, Z. et al. A novel nuclear protein, 5qNCA (LOC51780) is a candidate for the myeloid leukemia tumor suppressor gene on chromosome 5 band q31. Oncogene 20, 6946-6954

Section of Hematology/Oncology, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois 60607-7170, USA.
Oncogene (Impact Factor: 8.46). 11/2001; 20(47):6946-54. DOI: 10.1038/sj.onc.1204850
Source: PubMed


Interstitial deletion or loss of chromosome 5, del(5q) or -5, is a frequent finding in myeloid leukemias and myelodysplasias, suggesting the presence of a tumor suppressor gene within the deleted region. In our search for this gene, we identified a candidate, 5qNCA (LOC51780), which lies within a consistently-deleted segment of 5q31. 5qNCA expresses a 7.2-kb transcript with a 5286-bp open reading frame which is present at high levels in heart, skeletal muscle, kidney, placenta, and liver as well as CD34+ cells and AML cell lines. 5qNCA encodes a 191-kD nuclear protein which contains a highly-conserved C-terminus containing a zinc finger with the unique spacing Cys-X2-Cys-X7-His-X2-Cys-X2-Cys-X4-Cys-X2-Cys and a jmjC domain, which is often found in proteins that regulate chromatin remodeling. Expression of 5qNCA in a del(5q) cell line results in suppression of clonogenic growth. Preliminary sequence results in AML and MDS samples and cell lines has revealed a possible mutation in the KG-1 cell line resulting in a THR to ALA substitution that has not been found in over 100 normal alleles to date. We propose 5qNCA is a good candidate for the del(5q) tumor suppressor gene based on its predicted function and growth suppressive activities, and suggest that further mutational and functional study of this interesting gene is warranted.

Download full-text


Available from: Stephen Horrigan
  • Source
    • "Knockout mice are viable but sterile and display an adult onset obesity phenotype [15], [16]. KDM3B has been suggested to be a candidate tumor suppressor gene [17]. JMJD1C has been described as an androgen receptor (AR)-interacting protein [18], and more recently, truncated mouse Jmjd1C has been proposed to be a H3K9me1/2 HDM [19]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Histone modifications play an important role in chromatin organization and gene regulation, and their interpretation is referred to as epigenetic control. The methylation levels of several lysine residues in histone tails are tightly controlled, and JmjC domain-containing proteins are one class of broadly expressed enzymes catalyzing methyl group removal. However, several JmjC proteins remain uncharacterized, gaps persist in understanding substrate recognition, and the integration of JmjC proteins into signaling pathways is just emerging. The KDM3 subfamily is an evolutionarily conserved group of histone demethylase proteins, thought to share lysine substrate specificity. Here we use a systematic approach to compare KDM3 subfamily members. We show that full-length KDM3A and KDM3B are H3K9me1/2 histone demethylases whereas we fail to observe histone demethylase activity for JMJD1C using immunocytochemical and biochemical approaches. Structure-function analyses revealed the importance of a single amino acid in KDM3A implicated in the catalytic activity towards H3K9me1/2 that is not conserved in JMJD1C. Moreover, we use quantitative proteomic analyses to identify subsets of the interactomes of the 3 proteins. Specific interactor candidates were identified for each of the three KDM3 subfamily members. Importantly, we find that SCAI, a known transcriptional repressor, interacts specifically with KDM3B. Taken together, we identify substantial differences in the biology of KDM3 histone demethylases, namely enzymatic activity and protein-protein interactions. Such comparative approaches pave the way to a better understanding of histone demethylase specificity and protein function at a systems level and are instrumental in identifying the more subtle differences between closely related proteins.
    Full-text · Article · Apr 2013 · PLoS ONE
  • Source
    • "However, whereas JHDM2A/JMJD1A/KDM3A, another member of the family, is known to demethylate H3K9me2 and H3K9me1, but not H3K9me3 (Yamane et al., 2006), the specificity of JHDM2B/KDM3B has not been defined further. The biological importance of the deletion of JHDM2B/KDM3B has been confirmed by experiments showing that ectopic expression of JHDM2B/KDM3B in cell lines derived from leukemias arising in 5q‐patients, inhibits their clonogenic growth (Hu et al., 2001). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Epigenetic modifications are heritable chromatin alterations that contribute to the temporal and spatial interpretation of the genome. The epigenetic information is conveyed through a multitude of chemical modifications, including DNA methylation, reversible modifications of histones, and ATP-dependent nucleosomal remodeling. Deregulation of the epigenetic machinery contributes to the development of several pathologies, including cancer. Chromatin modifications are multiple and interdependent and they are dynamically modulated in the course of various biological processes. Combinations of chromatin modifications give rise to a complex code that is superimposed on the genetic code embedded into the DNA sequence to regulate cell function. This review addresses the role of epigenetic modifications in cancer, focusing primarily on histone methylation marks and the enzymes catalyzing their removal.
    Full-text · Article · Feb 2009 · Advances in Cancer Research
  • Source
    • "Several genes in this overlapping region , includ - ing SMAD5 , KLHL3 , MYOT , KIF20A , CDC23 , CDC25C , JMJD1B , EGR1 , and CTNNA1 have been shown or suggested to have a tumor sup - pressor function ( Hejlik et al . , 1997 ; Zhao et al . , 1998 ; Godley et al . , 1999 ; Horrigan et al . , 2000 ; Hu et al . , 2001 ; Lai et al . , 2001 ; Liu et al . , 2007 ) . These results together with our findings of 5q23 . 2 - q31 . 2 deletions in PA and Ca - ex - PA sug - gest that a tumor suppressor gene of pathogenetic importance for these tumors is located within this region ( Bullerdiek et al . , 1990 ) . Whether any of the above - mentioned genes implica"
    [Show abstract] [Hide abstract]
    ABSTRACT: Carcinoma ex pleomorphic adenoma (Ca-ex-PA) is an epithelial malignancy developing within a benign salivary gland pleomorphic adenoma (PA). Here we have used genome-wide, high-resolution array-CGH, and fluorescence in situ hybridization to identify genes amplified in double min chromosomes and homogeneously staining regions in PA and Ca-ex-PA and to identify additional genomic imbalances characteristic of these tumor types. Ten of the 16 tumors analyzed showed amplification/gain of a 30-kb minimal common region, consisting of the 5'-part of HMGA2 (encoding the three DNA-binding domains). Coamplification of MDM2 was found in nine tumors. Five tumors had cryptic HMGA2-WIF1 gene fusions with amplification of the fusion oncogene in four tumors. Expression analysis of eight amplified candidate genes in 12q revealed that tumors with amplification/rearrangement of HMGA2 and MDM2 had significantly higher expression levels when compared with tumors without amplification. Analysis of individual HMGA2 exons showed that the expression of exons 3-5 were substantially reduced when compared with exons 1-2 in 9 of 10 tumors with HMGA2 activation, indicating that gene fusions and rearrangements of HMGA2 are common in tumors with amplification. In addition, recurrent amplifications/gains of 1q11-q32.1, 2p16.1-p12, 8q12.1, 8q22-24.1, and 20, and losses of 1p21.3-p21.1, 5q23.2-q31.2, 8p, 10q21.3, and 15q11.2 were identified. Collectively, our results identify HMGA2 and MDM2 as amplification targets in PA and Ca-ex-PA and suggest that amplification of 12q genes (in particular MDM2), deletions of 5q23.2-q31.2, gains of 8q12.1 (PLAG1) and 8q22.1-q24.1 (MYC), and amplification of ERBB2 may be of importance for malignant transformation of benign PA.
    Full-text · Article · Jan 2009 · Genes Chromosomes and Cancer
Show more