Skip to main content
NCBI home page
Nucleic Acids Research logoLink to Nucleic Acids Research
. 1993 Sep 11;21(18):4259–4267. doi: 10.1093/nar/21.18.4259

Organization, inducible-expression and chromosome localization of the human HMG-I(Y) nonhistone protein gene.

M Friedmann 1, L T Holth 1, H Y Zoghbi 1, R Reeves 1
PMCID: PMC310059  PMID: 8414980

Abstract

Members of the HMG-I(Y) family of mammalian nonhistone proteins are of importance because they have been demonstrated to bind specifically to the minor groove of A.T-rich sequences both in vitro and in vivo and to function as gene transcriptional regulatory proteins in vivo. Here we report the cloning, sequencing, characterization and chromosomal localization of the human HMG-I(Y) gene. The gene has several potential promoter/enhancer regions, a number of different transcription start sites and numerous alternatively spliced exons making it one of the most complex nonhistone chromatin protein-encoding genes so far reported. The putative promoter/enhancer regions each contain a number of conserved nucleotide sequences for potential binding of inducible regulatory transcription factors. Consistent with the presence of these conserved sequences, we found that transcription of the HMG-I(Y) gene is inducible in human lymphoid cells by factors such as phorbol esters and calcium ionophores. Detailed sequence analysis confirms our earlier suggestion that alternative splicing of precursor mRNAs gives rise to the major HMG-I and HMG-Y isoform proteins found in human cells. Furthermore, the gene's exon-intron arrangement fully accounts for all of the previously cloned human HMG-I(Y) cDNAs (1,2). Also of considerable interest is the fact that each of the three different DNA-binding domain peptides present in an individual HMG-I(Y) protein is coded for by sequences present on separate exons thus potentially allowing for exon 'shuffling' of these functional domains during evolution. And, finally, we localized the gene to the short arm of chromosome 6 (6p) in a region that is known to be involved in rearrangements, translocations and other abnormalities correlated with a number of human cancers.

Full text

PDF
4259

Images in this article

4264Image
on p.4264
4264Image
on p.4264

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Andreadis A., Gallego M. E., Nadal-Ginard B. Generation of protein isoform diversity by alternative splicing: mechanistic and biological implications. Annu Rev Cell Biol. 1987;3:207–242. doi: 10.1146/annurev.cb.03.110187.001231. [DOI] [PubMed] [Google Scholar]
  2. Arrick B. A., Lee A. L., Grendell R. L., Derynck R. Inhibition of translation of transforming growth factor-beta 3 mRNA by its 5' untranslated region. Mol Cell Biol. 1991 Sep;11(9):4306–4313. doi: 10.1128/mcb.11.9.4306. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bird A. P. CpG-rich islands and the function of DNA methylation. Nature. 1986 May 15;321(6067):209–213. doi: 10.1038/321209a0. [DOI] [PubMed] [Google Scholar]
  4. Bussemakers M. J., van de Ven W. J., Debruyne F. M., Schalken J. A. Identification of high mobility group protein I(Y) as potential progression marker for prostate cancer by differential hybridization analysis. Cancer Res. 1991 Jan 15;51(2):606–611. [PubMed] [Google Scholar]
  5. Bustin M., Lehn D. A., Landsman D. Structural features of the HMG chromosomal proteins and their genes. Biochim Biophys Acta. 1990 Jul 30;1049(3):231–243. doi: 10.1016/0167-4781(90)90092-g. [DOI] [PubMed] [Google Scholar]
  6. Davies B., Feo S., Heard E., Fried M. A strategy to detect and isolate an intron-containing gene in the presence of multiple processed pseudogenes. Proc Natl Acad Sci U S A. 1989 Sep;86(17):6691–6695. doi: 10.1073/pnas.86.17.6691. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Davisson M. T., Lalley P. A., Peters J., Doolittle D. P., Hillyard A. L., Searle A. G. Report of the comparative subcommittee for human and mouse homologies. Cytogenet Cell Genet. 1990;55(1-4):434–456. doi: 10.1159/000133026. [DOI] [PubMed] [Google Scholar]
  8. Disney J. E., Johnson K. R., Magnuson N. S., Sylvester S. R., Reeves R. High-mobility group protein HMG-I localizes to G/Q- and C-bands of human and mouse chromosomes. J Cell Biol. 1989 Nov;109(5):1975–1982. doi: 10.1083/jcb.109.5.1975. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Eckner R., Birnstiel M. L. Cloning of cDNAs coding for human HMG I and HMG Y proteins: both are capable of binding to the octamer sequence motif. Nucleic Acids Res. 1989 Aug 11;17(15):5947–5959. doi: 10.1093/nar/17.15.5947. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Elton T. S., Nissen M. S., Reeves R. Specific A . T DNA sequence binding of RP-HPLC purified HMG-I. Biochem Biophys Res Commun. 1987 Feb 27;143(1):260–265. doi: 10.1016/0006-291x(87)90659-0. [DOI] [PubMed] [Google Scholar]
  11. Elton T. S., Reeves R. Purification and postsynthetic modifications of Friend erythroleukemic cell high mobility group protein HMG-I. Anal Biochem. 1986 Aug 15;157(1):53–62. doi: 10.1016/0003-2697(86)90195-8. [DOI] [PubMed] [Google Scholar]
  12. Faisst S., Meyer S. Compilation of vertebrate-encoded transcription factors. Nucleic Acids Res. 1992 Jan 11;20(1):3–26. doi: 10.1093/nar/20.1.3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Fashena S. J., Reeves R., Ruddle N. H. A poly(dA-dT) upstream activating sequence binds high-mobility group I protein and contributes to lymphotoxin (tumor necrosis factor-beta) gene regulation. Mol Cell Biol. 1992 Feb;12(2):894–903. doi: 10.1128/mcb.12.2.894. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Giancotti V., Buratti E., Perissin L., Zorzet S., Balmain A., Portella G., Fusco A., Goodwin G. H. Analysis of the HMGI nuclear proteins in mouse neoplastic cells induced by different procedures. Exp Cell Res. 1989 Oct;184(2):538–545. doi: 10.1016/0014-4827(89)90352-2. [DOI] [PubMed] [Google Scholar]
  15. Giancotti V., Pani B., D'Andrea P., Berlingieri M. T., Di Fiore P. P., Fusco A., Vecchio G., Philp R., Crane-Robinson C., Nicolas R. H. Elevated levels of a specific class of nuclear phosphoproteins in cells transformed with v-ras and v-mos oncogenes and by cotransfection with c-myc and polyoma middle T genes. EMBO J. 1987 Jul;6(7):1981–1987. doi: 10.1002/j.1460-2075.1987.tb02461.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Gil G., Smith J. R., Goldstein J. L., Brown M. S. Optional exon in the 5'-untranslated region of 3-hydroxy-3-methylglutaryl coenzyme A synthase gene: conserved sequence and splicing pattern in humans and hamsters. Proc Natl Acad Sci U S A. 1987 Apr;84(7):1863–1866. doi: 10.1073/pnas.84.7.1863. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Green M. R. Biochemical mechanisms of constitutive and regulated pre-mRNA splicing. Annu Rev Cell Biol. 1991;7:559–599. doi: 10.1146/annurev.cb.07.110191.003015. [DOI] [PubMed] [Google Scholar]
  18. Hattori M., Sakaki Y. Dideoxy sequencing method using denatured plasmid templates. Anal Biochem. 1986 Feb 1;152(2):232–238. doi: 10.1016/0003-2697(86)90403-3. [DOI] [PubMed] [Google Scholar]
  19. Johnson K. R., Cook S. A., Davisson M. T. Chromosomal localization of the murine gene and two related sequences encoding high-mobility-group I and Y proteins. Genomics. 1992 Mar;12(3):503–509. doi: 10.1016/0888-7543(92)90441-t. [DOI] [PubMed] [Google Scholar]
  20. Johnson K. R., Disney J. E., Wyatt C. R., Reeves R. Expression of mRNAs encoding mammalian chromosomal proteins HMG-I and HMG-Y during cellular proliferation. Exp Cell Res. 1990 Mar;187(1):69–76. doi: 10.1016/0014-4827(90)90118-t. [DOI] [PubMed] [Google Scholar]
  21. Johnson K. R., Lehn D. A., Elton T. S., Barr P. J., Reeves R. Complete murine cDNA sequence, genomic structure, and tissue expression of the high mobility group protein HMG-I(Y). J Biol Chem. 1988 Dec 5;263(34):18338–18342. [PubMed] [Google Scholar]
  22. Johnson K. R., Lehn D. A., Reeves R. Alternative processing of mRNAs encoding mammalian chromosomal high-mobility-group proteins HMG-I and HMG-Y. Mol Cell Biol. 1989 May;9(5):2114–2123. doi: 10.1128/mcb.9.5.2114. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Ladner M. B., Martin G. A., Noble J. A., Nikoloff D. M., Tal R., Kawasaki E. S., White T. J. Human CSF-1: gene structure and alternative splicing of mRNA precursors. EMBO J. 1987 Sep;6(9):2693–2698. doi: 10.1002/j.1460-2075.1987.tb02561.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Lanahan A., Williams J. B., Sanders L. K., Nathans D. Growth factor-induced delayed early response genes. Mol Cell Biol. 1992 Sep;12(9):3919–3929. doi: 10.1128/mcb.12.9.3919. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Leff S. E., Rosenfeld M. G., Evans R. M. Complex transcriptional units: diversity in gene expression by alternative RNA processing. Annu Rev Biochem. 1986;55:1091–1117. doi: 10.1146/annurev.bi.55.070186.005303. [DOI] [PubMed] [Google Scholar]
  26. Lund T., Holtlund J., Fredriksen M., Laland S. G. On the presence of two new high mobility group-like proteins in HeLa S3 cells. FEBS Lett. 1983 Feb 21;152(2):163–167. doi: 10.1016/0014-5793(83)80370-6. [DOI] [PubMed] [Google Scholar]
  27. Lund T., Laland S. G. The metaphase specific phosphorylation of HMG I. Biochem Biophys Res Commun. 1990 Aug 31;171(1):342–347. doi: 10.1016/0006-291x(90)91399-d. [DOI] [PubMed] [Google Scholar]
  28. Manfioletti G., Giancotti V., Bandiera A., Buratti E., Sautière P., Cary P., Crane-Robinson C., Coles B., Goodwin G. H. cDNA cloning of the HMGI-C phosphoprotein, a nuclear protein associated with neoplastic and undifferentiated phenotypes. Nucleic Acids Res. 1991 Dec 25;19(24):6793–6797. doi: 10.1093/nar/19.24.6793. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Maxam A. M., Gilbert W. A new method for sequencing DNA. Proc Natl Acad Sci U S A. 1977 Feb;74(2):560–564. doi: 10.1073/pnas.74.2.560. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. McKeown M. Sex differentiation: the role of alternative splicing. Curr Opin Genet Dev. 1992 Apr;2(2):299–303. doi: 10.1016/s0959-437x(05)80288-6. [DOI] [PubMed] [Google Scholar]
  31. McRobert T. L., Rudduck C., Kees U. R., Garson O. M. Detection of MYCN amplification in three neuroblastoma cell lines by non-radioactive chromosomal in situ hybridization. Cancer Genet Cytogenet. 1992 Apr;59(2):128–134. doi: 10.1016/0165-4608(92)90206-n. [DOI] [PubMed] [Google Scholar]
  32. Meijer L., Ostvold A. C., Walass S. I., Lund T., Laland S. G. High-mobility-group proteins P1, I and Y as substrates of the M-phase-specific p34cdc2/cyclincdc13 kinase. Eur J Biochem. 1991 Mar 28;196(3):557–567. doi: 10.1111/j.1432-1033.1991.tb15850.x. [DOI] [PubMed] [Google Scholar]
  33. Miyanishi S., Ohno H. Characterization of a novel T-cell lymphoma cell line established from a patient with systemic lupus erythematosus-associated lymphoma. Cancer Genet Cytogenet. 1992 Apr;59(2):199–205. doi: 10.1016/0165-4608(92)90215-t. [DOI] [PubMed] [Google Scholar]
  34. Mount S. M. A catalogue of splice junction sequences. Nucleic Acids Res. 1982 Jan 22;10(2):459–472. doi: 10.1093/nar/10.2.459. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Nagarajan L., Louie E., Tsujimoto Y., ar-Rushdi A., Huebner K., Croce C. M. Localization of the human pim oncogene (PIM) to a region of chromosome 6 involved in translocations in acute leukemias. Proc Natl Acad Sci U S A. 1986 Apr;83(8):2556–2560. doi: 10.1073/pnas.83.8.2556. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Nissen M. S., Langan T. A., Reeves R. Phosphorylation by cdc2 kinase modulates DNA binding activity of high mobility group I nonhistone chromatin protein. J Biol Chem. 1991 Oct 25;266(30):19945–19952. [PubMed] [Google Scholar]
  37. Philip P., Geisler C., Hansen M. M., Hasselbalch H., Christensen B. E., Drivsholm A., Lund B., Nielsen J. B., Jensen K. B., Andersen E. Aberrations of chromosome 6 in 193 newly diagnosed untreated cases of chronic lymphocytic leukemia. Cancer Genet Cytogenet. 1991 May;53(1):35–43. doi: 10.1016/0165-4608(91)90112-8. [DOI] [PubMed] [Google Scholar]
  38. Radic M. Z., Saghbini M., Elton T. S., Reeves R., Hamkalo B. A. Hoechst 33258, distamycin A, and high mobility group protein I (HMG-I) compete for binding to mouse satellite DNA. Chromosoma. 1992 Oct;101(10):602–608. doi: 10.1007/BF00360537. [DOI] [PubMed] [Google Scholar]
  39. Reeves R. Chromatin changes during the cell cycle. Curr Opin Cell Biol. 1992 Jun;4(3):413–423. doi: 10.1016/0955-0674(92)90006-x. [DOI] [PubMed] [Google Scholar]
  40. Reeves R., Elton T. S., Nissen M. S., Lehn D., Johnson K. R. Posttranscriptional gene regulation and specific binding of the nonhistone protein HMG-I by the 3' untranslated region of bovine interleukin 2 cDNA. Proc Natl Acad Sci U S A. 1987 Sep;84(18):6531–6535. doi: 10.1073/pnas.84.18.6531. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Reeves R., Langan T. A., Nissen M. S. Phosphorylation of the DNA-binding domain of nonhistone high-mobility group I protein by cdc2 kinase: reduction of binding affinity. Proc Natl Acad Sci U S A. 1991 Mar 1;88(5):1671–1675. doi: 10.1073/pnas.88.5.1671. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Reeves R., Nissen M. S. The A.T-DNA-binding domain of mammalian high mobility group I chromosomal proteins. A novel peptide motif for recognizing DNA structure. J Biol Chem. 1990 May 25;265(15):8573–8582. [PubMed] [Google Scholar]
  43. Rio D. C. RNA processing. Curr Opin Cell Biol. 1992 Jun;4(3):444–452. doi: 10.1016/0955-0674(92)90010-a. [DOI] [PubMed] [Google Scholar]
  44. Rowley J. D., Potter D. Chromosomal banding patterns in acute nonlymphocytic leukemia. Blood. 1976 May;47(5):705–721. [PubMed] [Google Scholar]
  45. Skalnik D. G., Neufeld E. J. Sequence-specific binding of HMG-I(Y) to the proximal promoter of the gp91-phox gene. Biochem Biophys Res Commun. 1992 Sep 16;187(2):563–569. doi: 10.1016/0006-291x(92)91231-e. [DOI] [PubMed] [Google Scholar]
  46. Smith C. W., Patton J. G., Nadal-Ginard B. Alternative splicing in the control of gene expression. Annu Rev Genet. 1989;23:527–577. doi: 10.1146/annurev.ge.23.120189.002523. [DOI] [PubMed] [Google Scholar]
  47. Soekarman D., von Lindern M., Daenen S., de Jong B., Fonatsch C., Heinze B., Bartram C., Hagemeijer A., Grosveld G. The translocation (6;9) (p23;q34) shows consistent rearrangement of two genes and defines a myeloproliferative disorder with specific clinical features. Blood. 1992 Jun 1;79(11):2990–2997. [PubMed] [Google Scholar]
  48. Solomon M. J., Strauss F., Varshavsky A. A mammalian high mobility group protein recognizes any stretch of six A.T base pairs in duplex DNA. Proc Natl Acad Sci U S A. 1986 Mar;83(5):1276–1280. doi: 10.1073/pnas.83.5.1276. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Strauss F., Varshavsky A. A protein binds to a satellite DNA repeat at three specific sites that would be brought into mutual proximity by DNA folding in the nucleosome. Cell. 1984 Jul;37(3):889–901. doi: 10.1016/0092-8674(84)90424-0. [DOI] [PubMed] [Google Scholar]
  50. Testa J. R., Mintz U., Rowley J. D., Vardiman J. W., Golomb H. M. Evolution of karyotypes in acute nonlymphocytic leukemia. Cancer Res. 1979 Sep;39(9):3619–3627. [PubMed] [Google Scholar]
  51. Thanos D., Maniatis T. The high mobility group protein HMG I(Y) is required for NF-kappa B-dependent virus induction of the human IFN-beta gene. Cell. 1992 Nov 27;71(5):777–789. doi: 10.1016/0092-8674(92)90554-p. [DOI] [PubMed] [Google Scholar]
  52. Tkachuk D. C., Kohler S., Cleary M. L. Involvement of a homolog of Drosophila trithorax by 11q23 chromosomal translocations in acute leukemias. Cell. 1992 Nov 13;71(4):691–700. doi: 10.1016/0092-8674(92)90602-9. [DOI] [PubMed] [Google Scholar]
  53. Vermaelen K., Michaux J. L., Louwagie A., Van den Berghe H. Reciprocal translocation t(6;9)(p21;q33): a new characteristic chromosome anomaly in myeloid leukemias. Cancer Genet Cytogenet. 1983 Oct;10(2):125–131. doi: 10.1016/0165-4608(83)90115-2. [DOI] [PubMed] [Google Scholar]
  54. Wingett D., Reeves R., Magnuson N. S. Stability changes in pim-1 proto-oncogene mRNA after mitogen stimulation of normal lymphocytes. J Immunol. 1991 Nov 15;147(10):3653–3659. [PubMed] [Google Scholar]
  55. Zoghbi H. Y., Ballantyne C. M., O'Brien W. E., McCall A. E., Kwiatkowski T. J., Jr, Ledbetter S. A., Beaudet A. L. Deletion and linkage mapping of eight markers from the proximal short arm of chromosome 6. Genomics. 1990 Feb;6(2):352–357. doi: 10.1016/0888-7543(90)90576-g. [DOI] [PubMed] [Google Scholar]
  56. Zoghbi H. Y., McCall A. E., LeBorgne-Demarquoy F. Sixty-five radiation hybrids for the short arm of human chromosome 6: their value as a mapping panel and as a source for rapid isolation of new probes using repeat element-mediated PCR. Genomics. 1991 Apr;9(4):713–720. doi: 10.1016/0888-7543(91)90365-l. [DOI] [PubMed] [Google Scholar]

Articles from Nucleic Acids Research are provided here courtesy of Oxford University Press

RESOURCES