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Tumor Biology
Published in: Tumor Biology 1/2010

Open Access 01-01-2010 | Research Article

Pro-apoptotic and antiproliferative activity of human KCNRG, a putative tumor suppressor in 13q14 region

Authors: Aybike Birerdinc, Elizabeth Nohelty, Andrey Marakhonov, Ganiraju Manyam, Ivan Panov, Stephanie Coon, Eugene Nikitin, Mikhail Skoblov, Vikas Chandhoke, Ancha Baranova

Published in: Tumor Biology | Issue 1/2010

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Abstract

Deletion of 13q14.3 and a candidate gene KCNRG (potassium channel regulating gene) is the most frequent chromosomal abnormality in B-cell chronic lymphocytic leukemia and is a common finding in multiple myeloma (MM). KCNRG protein may interfere with the normal assembly of the K+ channel proteins causing the suppression of Kv currents. We aimed to examine possible role of KCNRG haploinsufficiency in chronic lymphocytic leukemia (CLL) and MM cells. We performed detailed genomic analysis of the KCNRG locus; studied effects of the stable overexpression of KCNRG isoforms in RPMI-8226, HL-60, and LnCaP cells; and evaluated relative expression of its transcripts in various human lymphomas. Three MM cell lines and 35 CLL PBL samples were screened for KCNRG mutations. KCNRG exerts growth suppressive and pro-apoptotic effects in HL-60, LnCaP, and RPMI-8226 cells. Direct sequencing of KCNRG exons revealed point mutation delT in RPMI-8226 cell line. Levels of major isoform of KCNRG mRNA are lower in DLBL lymphomas compared to normal PBL samples, while levels of its minor mRNA are decreased across the broad range of the lymphoma types. The haploinsufficiency of KCNRG might be relevant to the progression of CLL and MM at least in a subset of patients.
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Literature
1.
Caporaso N, Marti GE, Goldin L. Perspectives on familial chronic lymphocytic leukaemia: genes and the environment. Semin Hematol. 2004;41:201–6.CrossRefPubMed
2.
Redaelli A, Laskin BL, Stephens JM, Botteman MF, Pashos CL. The clinical and epidemiological burden of chronic lymphocytic leukaemia. Eur J Cancer Care (Engl). 2004;13:279–87.CrossRef
3.
Danilov AV, Danilova OV, Klein AK, Huber BT. Molecular pathogenesis of chronic lymphocytic leukaemia. Curr Mol Med. 2006;6:665–75.CrossRefPubMed
4.
Gale RP, Foon KA. Biology of chronic lymphocytic leukaemia. Semin Hematol. 1987;24:209–29.PubMed
5.
Ougolkov AV, Bone ND, Fernandez-Zapico ME, Kay NE, Billadeau DD. Inhibition of glycogen synthase kinase-3 activity leads to epigenetic silencing of nuclear factor kappaB target genes and induction of apoptosis in chronic lymphocytic leukaemia B cells. Blood. 2007;110:735–42.CrossRefPubMed
6.
Iglesias-Serret D, de Frias M, Santidrian AF, Coll-Mulet L, Cosialls AM, Barragán M, et al. Regulation of the proapoptotic BH3-only protein BIM by glucocorticoids, survival signals and proteasome in chronic lymphocytic leukaemia cells. Leukemia. 2007;21:281–7.CrossRefPubMed
7.
Bueso-Ramos CE, Ferrajoli A, Medeiros LJ, Keating MJ, Estrov Z. Aberrant morphology, proliferation, and apoptosis of B-cell chronic lymphocytic leukaemia cells. Hematology. 2004;9:279–86.CrossRefPubMed
8.
Chiorazzi N, Ferrarini M. Evolving view of the in-vivo kinetics of chronic lymphocytic leukaemia B cells. Hematology Am Soc Hematol Educ Program. 2006;273–8:512.
9.
Liu Y, Corcoran M, Rasool O, Ivanova G, Ibbotson R, Grandér D, et al. Cloning of two candidate tumor suppressor genes within a 10 kb region on chromosome 13q14, frequently deleted in chronic lymphocytic leukaemia. Oncogene. 1997;15:2463–73.CrossRefPubMed
10.
Dohner H, Stilgenbauer S, Dohner K, Bentz M, Lichter P. Chromosome aberrations in B-cell chronic lymphocytic leukaemia: reassessment based on molecular cytogenetic analysis. J Mol Med. 1999;77:266–81.CrossRefPubMed
11.
Rosenwald A, Ott G, Krumdiek AK, Dreyling MH, Katzenberger T, Kalla J, et al. A biological role for deletions in chromosomal band 13q14 in mantle cell and peripheral t-cell lymphomas? Genes, Chromosomes Cancer. 1999;26:210–4.CrossRefPubMed
12.
Harrison CJ, Mazzullo H, Cheung KL, Gerrard G, Jalali GR, Mehta A, et al. Cytogenetics of multiple myeloma: interpretation of fluorescence in situ hybridization results. Br J Haematol. 2003;120:944–52.CrossRefPubMed
13.
Elnenaei MO, Hamoudi RA, Swansbury J, Gruszka-Westwood AM, Brito-Babapulle V, Matutes E, et al. Delineation of the minimal region of loss at 13q14 in multiple myeloma. Genes Chromosomes Cancer. 2003;36:99–106.CrossRefPubMed
14.
Lu W, Takahashi H, Furusato M, Maekawa S, Nakano M, Meng C, et al. Allelotyping analysis at chromosome 13q of high-grade prostatic intraepithelial neoplasia and clinically insignificant and significant prostate cancers. Prostate. 2006;66:405–12.CrossRefPubMed
15.
Rowntree C, Duke V, Panayiotidis P, Kotsi P, Palmisano GL, Hoffbrand AV, et al. Deletion analysis of chromosome 13q14.3 and characterisation of an alternative splice form of LEU1 in B cell chronic lymphocytic leukaemia. Leukemia. 2002;16:1267–75.CrossRefPubMed
16.
Tyybakinoja A, Vilpo J, Knuutila S. High-resolution oligonucleotide array-CGH pinpoints genes involved in cryptic losses in chronic lymphocytic leukaemia. Cytogenet Genome Res. 2007;118:8–12.CrossRefPubMed
17.
Kapanadze B, Kashuba V, Baranova A, Rasool O, van Everdink W, Liu Y, et al. A cosmid and cDNA fine physical map of a human chromosome 13q14 region frequently lost in B-cell chronic lymphocytic leukaemia and identification of a new putative tumor suppressor gene, Leu5. FEBS Lett. 1998;426:266–70.CrossRefPubMed
18.
Calin GA, Dumitru CD, Shimizu M, Bichi R, Zupo S, Noch E, et al. Frequent deletions and down-regulation of micro-RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukaemia. Proc Natl Acad Sci USA. 2002;99:15524–9.CrossRefPubMed
19.
Baranova A, Hammarsund M, Ivanov D, Skoblov M, Sangfelt O, Corcoran M, et al. Distinct organization of the candidate tumor suppressor gene RFP2 in human and mouse: multiple mRNA isoforms in both species- and human-specific antisense transcript RFP2OS. Gene. 2003;321:103–12.CrossRefPubMed
20.
Wolf S, Mertens D, Schaffner C, Korz C, Korz C, Döhner H, et al. B-cell neoplasia associated gene with multiple splicing (BCMS): the candidate B-CLL gene on 13q14 comprises more than 560 kb covering all critical regions. Hum Mol Genet. 2001;10:1275–85.CrossRefPubMed
21.
van Everdink WJ, Baranova A, Lummen C, Tyazhelova T, Looman MW, Ivanov D, et al. RFP2, c13ORF1, and FAM10A4 are the most likely tumor suppressor gene candidates for B-cell chronic lymphocytic leukaemia. Cancer Genet Cytogenet. 2003;146:48–57.CrossRefPubMed
22.
Mertens D, Wolf S, Schroeter P, Schaffner C, Döhner H, Stilgenbauer S, et al. Down-regulation of candidate tumor suppressor genes within chromosome band 13q14.3 is independent of the DNA methylation pattern in B-cell chronic lymphocytic leukaemia. Blood. 2002;99:4116–21.CrossRefPubMed
23.
Ivanov DV, Tyazhelova TV, Lemonnier L, Kononenko N, Pestova AA, Nikitin EA, et al. A new human gene KCNRG encoding potassium channel regulating protein is a cancer suppressor gene candidate located in 13q14.3. FEBS Lett. 2003;539:156–60.CrossRefPubMed
24.
Rybalchenko V, Prevarskaya N, Van Coppenolle F, Legrand G, Lemonnier L, Le Bourhis X, et al. Verapamil inhibits proliferation of LNCaP human prostate cancer cells influencing K+ channel gating. Mol Pharmacol. 2001;59:1376–87.PubMed
25.
Lewis RS, Cahalan MD. Potassium and calcium channels in lymphocytes. Annu Rev Immunol. 1995;13:623–53.CrossRefPubMed
26.
Smith GA, Tsui HW, Newell EW, Jiang X, Zhu XP, Tsui FW, et al. Functional up-regulation of HERG K+ channels in neoplastic hematopoietic cells. J Biol Chem. 2002;277:18528–34.CrossRefPubMed
27.
Sambrook J, Fritsch EF, Maniatis T. Molecular cloning: a laboratory manual. Cold Spring Harbor: Cold Spring Harbor Laboratory Press; 1989.
28.
Kim YH, Proust JJ, Buchholz MJ, Chrest FJ, Nordin AA. Expression of the murine homologue of the cell cycle control protein p34cdc2 in T lymphocytes. J Immunol. 1992;149:17–23.PubMed
29.
Grace MB, McLeland CB, Gagliardi SJ, Smith JM, Jackson WE, Blakely WF. Quantitative RT-PCR assay using simultaneous measurement of four fluorophores for radiation-responsive gene targets. Clin Chem. 2003;49:1467–75.CrossRefPubMed
30.
Lerner M, Corcoran M, Cepeda D, Nielsen ML, Zubarev R, Pontén F, et al. The RBCC gene RFP2 (Leu5) encodes a novel transmembrane E3 ubiquitin ligase involved in ERAD. Mol Biol Cell. 2007;18:1670–82.CrossRefPubMed
31.
Skoblov M, Shakhbazov K, Oshchepkov D, Ivanov D, Guskova A, Ivanov D, et al. Human RFP2 gene promoter: unique structure and unusual strength. Biochem Biophys Res Commun. 2006;342:859–66.CrossRefPubMed
32.
Stogios PJ, Downs GS, Jauhal JJ, Nandra SK, Privé GG. Sequence and structural analysis of BTB domain proteins. Genome Biol. 2005;6(10):R82.CrossRefPubMed
33.
Raveche ES, Salerno E, Scaglione BJ, Manohar V, Abbasi F, Lin YC, et al. Abnormal microRNA-16 locus with synteny to human 13q14 linked to CLL in NZB mice. Blood. 2007;109:5079–86.CrossRefPubMed
34.
Cho YG, Kim CJ, Song JH, Rhie DJ, Park YK, Kim SY, et al. Genetic and expression analysis of the KCNRG gene in hepatocellular carcinomas. Exp Mol Med. 2006;38:247–55.PubMed
35.
Liu JP, Liu NS, Yuan HY, Guo Q, Lu H, Li YY. Human homologue of SETA binding protein 1 interacts with cathepsin B and participates in TNF-Induced apoptosis in ovarian cancer cells. Mol Cell Biochem. 2006;292:189–95.CrossRefPubMed
36.
Argenti B, Gallo R, Di Marcotullio L, Ferretti E, Napolitano M, Canterini S, et al. Hedgehog antagonist REN(KCTD11) regulates proliferation and apoptosis of developing granule cell progenitors. J Neurosci. 2005;25:8338–46.CrossRefPubMed
37.
Suehara Y, Kondo T, Seki K, Shibata T, Fujii K, Gotoh M, et al. Pfetin as a prognostic biomarker of gastrointestinal stromal tumors revealed by proteomics. Clin Cancer Res. 2008;14:1707–17.CrossRefPubMed
Metadata
Title
Pro-apoptotic and antiproliferative activity of human KCNRG, a putative tumor suppressor in 13q14 region
Authors
Aybike Birerdinc
Elizabeth Nohelty
Andrey Marakhonov
Ganiraju Manyam
Ivan Panov
Stephanie Coon
Eugene Nikitin
Mikhail Skoblov
Vikas Chandhoke
Ancha Baranova
Publication date
01-01-2010
Publisher
Springer Netherlands
Published in
Tumor Biology / Issue 1/2010
Print ISSN: 1010-4283
Electronic ISSN: 1423-0380
DOI
https://doi.org/10.1007/s13277-009-0005-0

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