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Japanese Journal of Cancer Research : Gann logoLink to Japanese Journal of Cancer Research : Gann
. 2002 Feb;93(2):167–177. doi: 10.1111/j.1349-7006.2002.tb01255.x

Expression of Hqk Encoding a KH RNA Binding Protein Is Altered in Human Glioma

Zheng Zhe Li 1, Tatsuya Kondo 1, Tomoaki Murata 1,2, Thomas A Ebersole 3, Torn Nishi 4, Kenji Tada 4, Yukitaka Ushio 4, Ken‐ichi Yamamura 1, Kuniya Abe 1,
PMCID: PMC5926958  PMID: 11856480

Abstract

The quaking gene family encodes single KH domain RNA‐binding proteins that play vital roles in cell differentiation, proliferation, and apoptotic processes. The human quaking gene, Hqk, maps to 6q25–q26, where cytogenetic alterations associated with a variety of human malignancies, including gliomas have been reported. To assess possible relationships of Hqk with human diseases such as glial tumors, we first isolated the Hqk gene, characterized its structure and expression pattern, and carried out mutational analysis of Hqk in primary tumor samples. The Hqk gene contains 8 exons spanning a ∼200 kb genomic region, and generating at least four alternatively spliced transcripts, Hqk–5, Hqk–6, Hqk–7 and Hqk–7B, of which Hqk–7 is abundantly expressed in brain. Analysis of primary tumors demonstrated a high incidence of expression alterations of Hqk in gliomas (30%; 6/20), but not in other tumors such as schwannomas (0/3), or meningiomas (0/8). Among the tumor samples showing expression alterations, two were devoid of all three major transcripts, one was missing only the Hqk–5 message, and only the Hqk–7 message was absent in two cases. Our results thus imply the involvement of Hqk in human glial tumor progression.

Keywords: quaking, Gene structure, RNA binding protein, Glioma

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REFERENCES

  • 1.Ebersole , T. A. , Chen , Q. , Justice , M. J. and Artzt , K.The quaking gene product necessary in embryogenesis and myelination combines features of RNA binding and signal transduction proteins . Nat. Genet , 12 , 260 – 265 ( 1996. ). [DOI] [PubMed] [Google Scholar]
  • 2.Kondo , T. , Furuta , T. , Mitsunaga , K. , Ebersole , T. A. , Shichiri , M. , Wu , J. , Artzt , K. , Yamamura , K. and Abe , K.Genomic organization and expression analysis of the mouse qkl locus . Mamm. Genome , 10 , 662 – 669 ( 1999. ). [DOI] [PubMed] [Google Scholar]
  • 3.Sidman , R. L. , Dickie , M. M. and Apple , S. H.Mutant mice (quaking and jimpy) with deficient myelination in the central nervous system . Science , 144 , 309 – 312 ( 1964. ). [DOI] [PubMed] [Google Scholar]
  • 4.Hardy , R. J.Molecular defects in the dysmyelinating mutant quaking . J. Neurosci. Res. , 51 , 417 – 422 ( 1998. ). [DOI] [PubMed] [Google Scholar]
  • 5.Samorajski , T. , Friede , R. L. and Reimer , P. R.Hypomyelination in the quaking mouse. A model for the analysis of disturbed myelin formaton . J. Neuropathol. Exp. Neural. , 29 , 507 – 523 ( 1970. ). [DOI] [PubMed] [Google Scholar]
  • 6.Hardy , R. J. , Loushin , C. L. , Friedrich , V. L. , Jr. , Chen , Q. , Ebersole , T. A. , Lazzarini , R. A. and Artzt , K.Neural cell type‐specific expression of QKI proteins is altered in the quakingviable mutant mice . J. Neurosci. , 16 , 7941 – 7949 ( 1996. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Siomi , H. , Matunis , M. J. , Michael , W. M. and Dreyfuss , G.The pre‐mRNA binding K protein contains a novel evolutionarily conserved motif . Nucleic Acids Res. , 21 , 1193 – 1198 ( 1993. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Gibson , T. J. , Thompson , J. D. and Heringa , J.The KH domain occurs in a diverse set of RNA‐binding proteins that include the antiterminator NursA and is probably involved in binding to nucleic acid . FEBS Lett. , 324 , 361 – 366 ( 1993. ). [DOI] [PubMed] [Google Scholar]
  • 9.Musco , G. , Stier , G. , Joseph , C. , Morelli , M. A. C. , Nilges , M. , Gibson , T. J. and Pastore , A.Three‐dimentional structure and stability of the KH domain: molecular insights into the fragile × syndrome . Cell , 85 , 237 – 245 ( 1996. ). [DOI] [PubMed] [Google Scholar]
  • 10.Vernet , C. and Artzt , K.STAR, a gene family involved in signal transduction and activation of RNA . Trends Genet. , 13 , 479 – 484 ( 1997. ). [DOI] [PubMed] [Google Scholar]
  • 11.Cruz‐Alvarez , M. and Pellicer , A.Cloning of a full length complementary cDNA for a Anemia salina glycine‐rich protein . J. Biol. Chem. , 271 , 13377 – 13380 ( 1987. ). [PubMed] [Google Scholar]
  • 12.Wong , G. , Muller , O. , Clark , R. , Conroy , L. , Moran , M. F. , Polakis , P. and McCormick , F.Molecular cloning and nucleic acid binding properties of the GAP‐associated tyrosine phosphoprotein p62 . Cell , 69 , 551 – 558 ( 1992. ). [DOI] [PubMed] [Google Scholar]
  • 13.Jones , A. R. and Schedl , T.Mutations in gld–1, a female germ cell‐specific tumor suppressor gene in Caenorhabditis elegans, affect a conserved domain also found in Src‐associated protein Sam68 . Genes Dev. , 9 , 1491 – 1504 ( 1995. ). [DOI] [PubMed] [Google Scholar]
  • 14.Courtneidge , R. and Fumagalli , S.A mitotic function for Src ? Trends Cell Biol. , 4 , 345 – 347 ( 1994. ). [DOI] [PubMed] [Google Scholar]
  • 15.Taylor , S. J. and Shalloway , D.An RNA‐binding protein associated with Src through its SH2 and SH3 domains in mitosis . Nature , 368 , 867 – 871 ( 1994. ). [DOI] [PubMed] [Google Scholar]
  • 16.Francis , R. , Barton , M. K. , Kimbel , J. and Schedl , T.gld–1, a tumor suppressor gene required for oocyte development in Caenorhabditis elegans . Genetics , 139 , 579 – 606 ( 1995. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Francis , R. , Maine , E. and Schedl , T.Analysis of the multiple roles of gld–1 in germline development: interactions with the sex determination cascade and the gpl–1 signaling pathway . Genetics , 139 , 607 – 630 ( 1995. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Baehrecke , E. H.Who encodes a KH RNA binding protein that functions in muscle development . Development , 124 , 1323 – 1332 ( 1997. ). [DOI] [PubMed] [Google Scholar]
  • 19.Zaffran , S. , Astier , M. , Gratecos , D. and Semeriva , M.The held out wings (how) Drosophila gene encodes a putative RNA‐binding protein involved in the control of muscular and cardiac activity . Development , 124 , 2087 – 2098 ( 1997. ). [DOI] [PubMed] [Google Scholar]
  • 20.Zorn , A. M. and Krieg , P. A.The KH domain protein encoded by quaking functions as a dimer and is essential for notochord development in Xenopus embryos . Genes Dev. , 11 , 2176 – 2190 ( 1997. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Jones , A. R. , Francis , R. and Schedl , T.GLD–1, a cytoplasmic protein essential for oocyte differentiation, shows stage‐ and sex‐specific expression during Caenorhabditis elegans germline development . Dev. Biol. , 180 , 165 – 183 ( 1996. ). [DOI] [PubMed] [Google Scholar]
  • 22.Kaname , T. , Kondo , T. , Imanaka , T. , Suganuma , T. , Suzuki , M. , Ebersole , T. A. , Artzt , K. , Yamamura , K. and Abe , K. In preparation .
  • 23.Justice , M. J. and Bode , V. C.Three ENU‐induced alleles of the murine quaking locus are recessive embryonic lethal mutations . Genet. Res. , 51 , 95 – 102 ( 1988. ). [DOI] [PubMed] [Google Scholar]
  • 24.Li , Z. H. , Takakura , N. , Oike , Y. , Suda , T. , Kaname , T. , Artzt , K. , Yamamura , K. and Abe , K. In preparation .
  • 25.Zorn , A. M. , Grow , M. , Patterson , K. D. , Ebersole , T. A. , Chen , Q. , Artzt , K. and Krieg , P. A.Remarkable sequence conservation of transcripts encoding amphibian and mammalian homologues of quaking, a KH domain RNA‐binding protein . Gene , 188 , 199 – 206 ( 1997. ). [DOI] [PubMed] [Google Scholar]
  • 26.De Boulle , K. , Verkerk , A. J. , Reyniers , E. , Vits , L. , Hendrickx , J. , Van Roy , B. , Van den Bos , F. , de Grassff , E. , Oostra , B. A. and Willems , P. J.A point mutation in FMR–1 gene associated with fragile × mental retardation . Nat. Genet , 3 , 31 – 35 ( 1993. ). [DOI] [PubMed] [Google Scholar]
  • 27.Ashley , C. , Wilkinson , K. D. , Reines , D. and Warren , S. T.FMR 1 protein: conserved RNP family domains and selective RNA binding . Science , 262 , 563 – 566 ( 1993. ). [DOI] [PubMed] [Google Scholar]
  • 28.Gibson , T. J. , Rice , P. M. , Thompson , J. D. and Heringe , J.KH domains within the FMR1 sequence suggest that fragile × syndrome stems from a defect in RNA matabolism . Trends Biochem. Sci. , 18 , 331 – 333 ( 1993. ). [DOI] [PubMed] [Google Scholar]
  • 29.Siomi , H. , Choi , M. C. , Nussbaum , R. L. and Dreyfuss , G.The protein product of the fragile × gene, has characteristics of an RNA‐binding protein . Cell , 74 , 291 – 298 ( 1993. ). [DOI] [PubMed] [Google Scholar]
  • 30.Siomi , H. , Choi , M. , Siomi , M. C. , Nussbaum , R. L. and Dreyfuss , G.Essential role for KH domains in RNA‐binding: impaired RNA binding by a mutation in the KH domain of FMR1 that causes fragile × syndrome . Cell , 77 , 33 – 39 ( 1994. ). [DOI] [PubMed] [Google Scholar]
  • 31.Muller‐Pillasch , R , Lacher , U. , Wallrapp , C. , Micha , A. , Zimmerhackl , F. , Hameister , H. , Varga , G. , Friess , H. , Buchler , M. , Beger , H. G. , Vila , M. R. , Adler , G. and Gress , T. M.Cloning of a gene highly overexpressed in cancer coding for a novel KH‐domain containing protein . Oncogene , 14 , 2729 – 2733 ( 1997. ). [DOI] [PubMed] [Google Scholar]
  • 32.Zhang , J. Y. , Chan , E. K. L. , Peng , X. X. and Tan , E. M.A novel cytoplasmic protein with RNA‐binding motifs is an autoantigen in human hepatocellular carcinoma . J. Exp. Med. , 189 , 1101 – 1110 ( 1999. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Pilotte , J. , Larocque , D. and Richard , S.Nuclear translocation controlled by alternatively spliced isoforms inactivates the QUAKING apoptotic inducer . Genes Dev. , 15 , 845 – 858 ( 2001. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Schwartz , S. , Zhang , Z. , Frazer , K. A. , Smit , A. , Riemer , C. , Bouck , J. , Gibbs , R. , Hardison , R. and Miller , W.PipMarker‐a web server for aligning two genomic DNA sequences . Genome Res. , 10 , 577 – 586 ( 2000. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Miyakawa , A. , Ichimura , K. , Schmidt , E. E. , Vrmeh‐Ziaie , S. and Collins , V. P.Multiple deleted regions on the long arm of chromosome 6 in astrocytic tumours . Br. J. Cancer , 82 , 543 – 549 ( 2000. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Liang , B. C. , Ross , D. A. , Greenberg , H. S. , Meltzer , P. S. and Trent , J. M.Evidence of allelic imbalance of chromosome 6 in human astrocytomas . Neurology , 44 , 533 – 536 ( 1994. ). [DOI] [PubMed] [Google Scholar]
  • 37.Mitelman , F. , Mertens , F. and Johansson , B.A breakpoint map of recurrent chromosomal rearrangements in human neoplasia . Nat. Genet. (Special Issue), April , 417 – 474 ( 1997. ). [DOI] [PubMed] [Google Scholar]
  • 38.Trent , J. M. , Stanbridge , E. J. , McBride , H. L. , Meese , E. U. , Casey , G. , Araujo , D. E. , Witkowski , C. M. and Nagle , R. B.Tumorigenicity in human melanoma cell lines controlled by introduction of human chromosome 6 . Science , 247 , 568 – 571 ( 1990. ). [DOI] [PubMed] [Google Scholar]
  • 39.Zhu , J. and Chen , X.MCG10, a novel p53 target gene that encodes a KH domain RNA‐binding protein, is capable of inducing apoptosis and cell cycle arrest in G2–M . Mol. Cell Biol. , 20 , 5602 – 5618 ( 2000. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40.Tola , M. , Iizuka , Y. , Yu , W. J. , Imai , T. , Ikeda , E. , Yoshida , K. , Kawase , T. , Kawakami , Y. , Okano , H. and Uyemura , K.Expression of the neural RNA‐binding protein Musashi 1 in human gliomas . Glia , 34 , 1 – 7 ( 2001. ). [DOI] [PubMed] [Google Scholar]
  • 41.Kane , M. , Loda , M. , Gaida , G. , Lipman , J. , Mishra , R. , Goldman , H. , Jessup , J. M. and Kolodner , R.Methylaton of the hMLH1 promoter correlates with lack of expression of hMLH1 in sporadic colon tumors and mismatch repair‐defective human tumor cell lines . Cancer Res. , 57 , 808 – 811 ( 1997. ). [PubMed] [Google Scholar]

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