Abstract
Acis-acting interference between gene activities, which occurs when two genes lie on the same DNA strand and have an Intergenic distance less than a defined length, was previously deduced when chromo-somal organizations of various higher eukaryote nuclear genes in clusters were compared. In order to investigate such an interference due to arrangement of genes along chromosomes, we have isolated a few cell lines which possessed (i) human mutated c-H-ras fused with the mouse mammary tumour virus long terminal repeat and (ii) theE. coli xanthine-guanine phosphoribosyltransferase (gpt) gene with the SV40 promoter, on the same or on different DNA strands, separated by a short intergenic distance or unlinked. Since the cancerous phenotype of a cell can be readily identified due to c-H-ras expression, we examined in these cell lines whether continuous c-H-ras expression, induced by dexamethasone, is disturbed through acis-acting gene-to-gene interaction when the expression of the neighbouringgpt gene is enforced and as a result, the cancerous state of a cell is converted to the ‘normal’ state. The enforced expression of the neighbouringgpt gene was shown to alter c-H-ras expression, and thus reversible conversion of a cell between cancerous and normal states occurred only when the cell possessed an optimum number of the gene pair, in which both c-H-ras and thegpt gene were on the same DNA strand. This implies that the spatial arrangement of genes in chromosomes plays an important role in the regulation of gene expression in a cluster.
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References
Barbacid M (1987)ras genes.Annu Rev Biochem 56: 779–827.
Bishop JM (1983) Cellular oncogenes and retroviruses.Annu Rev Biochem 52: 301–354.
Capon DJ, Chen EY, Levinson AD, Seeburg PH, Goeddel V (1983) Complete nucleotide sequence of the T24 human bladder carcinoma oncogenes and its normal homologue.Nature 302 33–37.
Contente S, Kenyon K, Rimoldi D, Friedman RM (1990) Expression of generrg is associated with reversion of NIH 3T3 transformed by LTR-c-Hras.Science 249: 796–798.
Curtin MC, Murphy M, Costa-Giomi MPet al. (1987) Independent regulation of tumor necrosis factor and lymphotoxin production by human peripheral blood lymphocytes.J Exp Med 165: 1581–1594.
Darbré P, Page M, King RJB (1986) Androgen regulation by the long terminal repeat of mouse mammary tumour virus.Mol Cell Biol 6: 2847–2854.
Emerman M, Temin H (1984) Genes with promoters in retrovirus vectors can be independently suppressed by an epigenetic mechanism.Cell 39: 459–567.
Emerman M, Temin H (1986a) Quantitative analysis of gene suppression in integrated retrovirus vectors.Mol Cell Biol 6: 792–800.
Emerman M, Temin H (1986b) Comparison of promoter suppression in avian and murine retrovirus vectors.Nucleic Acids Res 14: 9381–9396.
Goeddel DV, Aggarwal BB, Gray PWet al. (1986) Tumor necrosis factors: gene structure and biological activities.Cold Spring Harbor Symp Quant Biol 51: 597–609.
Gunning P, Ponte P, Okayama Het al. (1983) Isolation and characterization of full-length cDNA clones for humanα-,β- andγ-actin mRNA: skeletal but not cytoplasmic actins have an amino-terminal cysteine that is subsequently removed.Mol Cell Biol 3: 787–795.
Huang H-JS, Yee J-K, Shew J-Yet al. (1988) Suppression of the neoplastic phenotype by replacement of the RB gene in human cancer cells.Science 242: 1563–1566.
Jaggi R, Salmons B, Muellener D, Groner B (1986) The v-mos and H-ras oncogene expression represses glucocorticoid hormone-dependent transcription from the mouse mammary tumour virus LTR.EMBO J 5: 2609–2616.
Kelso A, Metcalf O, Gough NM (1986). Independent regulation of granulocyte-macrophage colony-stimulating factor and multi-lineage colony-stimulating factor production in T lymphocyte clones.J Immunol 136: 1718–1725.
Kitayama H, Sugimoto Y, Matsuzaki T, Ikawa Y, Noda M (1989) Aras-related gene with transformation suppressor activity.Cell 56: 77–84.
Krzyzosiak WJ, Shindo-Okada N, Teshima H, Nakajima KS, Nishimura K (1992) Isolation of gene specifically expressed in flat revertant cells derived from activatedras-trans-formed NIH 3T3 cells by treatment with azatyrosine.Proc Natl Acad Sci USA 89: 4879–4883.
Lee S, Young IG (1989) Fine-structure mapping of the murine IL-3 and GM-CSF genes by pulse-field gel electrophoresis and molecular cloning.Genomics 5: 359–362.
Lomprè AM, Nadal-Ginard BV, Mahdavi V (1984) Expression of the cardiac ventricularα- andβ-myosin heavy chain genes is developmentally and hormonally regulated.J Biol Chem 259: 6437–6446.
Mahdavi V, Chambers AP, Nadal-Ginard B (1984) Cardiacα-andβ-myosin heavy chain genes are organised in tandem.Proc Natl Acad Sci USA 81: 2626–2630.
Mintz B, Illmensee K (1975) Normal genetically mosaic mice produced from malignant teratocarcinoma cells.Proc Natl Acad Sci USA 72: 3585–3589.
Mulligan RC, Berg P (1980) Expression of a bacterial gene in mammalian cells.Science 209: 1422–1427.
Mulligan RC, Berg P (1981) Selection for animal cells that express theEscherichia coli gene coding for xanthine-guanine phosphoribosyltransferase.Proc Natl Acad Sci USA 78: 2072- 2076.
Nakayasu M, Shima H, Aonuma Set al. (1988) Deletion of transfected oncogenes from NIH 3T3 transformants by inhibitors of poly (ADP-ribose) polymerase.Proc Natl Acad Sci USA 85: 9066–9070.
Naora H (1986) Gene ecology. A novel regulatory system in gene expression network.Biol Forum 79: 345–371.
Naora H, Deacon NJ (1982) Clustered genes require extragenic territorial DNA sequences.Differentiation 21: 1–6.
Pulciani S, Santos E, Long LK, Sorrentino V, Barbacid M (1985)ras gene amplification and malignant transformation.Mol Cell Biol 5: 2836–2841.
Rubin H, Xu K (1989) Evidence for the progressive and adaptive nature of spontaneous transformation in the NIH 3T3 cell line.Proc Natl Acad Sci USA 86: 1860–1864.
Sakai R, Ikeda I, Kitani Het al. (1989) Flat reversion by okadaic acid ofraf andret-II transformants.Proc Natl Acad Sci USA 86: 9946–9950.
Slamon DJ, De Kernio JB, Verma IM, Cline MJ (1984) Expression of cellular oncogenes in human malignancies.Science 224: 256–262.
Spandidos DA, Kerr IB (1984) Elevated expression of the humanras oncogene family in premalignant and malignant tumors of the colorectum.Br J Cancer 49: 681–688.
Sung S-SJ, Bjorndahl JM, Wang CY, Kao HT, Fu SM (1988) Production of tumor necroses factor/cachectin by human T cell lines and peripheral blood T lymphocytes stimulated by phorbol myristate acetate and anti-CD3 antibody.J Exp Med 167: 937–953.
Trojan J, Blossey BK, Johnson TRet al. (1992) Loss of tumorigenicity of rat glioblastoma directed by episome-based antisense cDNA transcription of insulin-like growth factor. I.Proc Natl Acad Sci USA 89: 4874–4878.
Wright WE, Pereira-Smith OM, Shay JW (1989) Reversible cellular senescence: implications for immortalization of normal human diploid fibroblasts.Mol Cell Biol 9: 3089–3092.
Xu Z-Z, Miyahara K, Liszczynsky H, Seno S, Naora H (1991a) Reversible conversion of cells between cancerous and normal states.Proc Japan Acad 67: 11–15.
Xu Z-Z, Miyahara K, Liszczynsky H, Seno S, Naora H (1991b) An optimum dose of c-H-ras is a prerequisite for hormonedependent conversion of a cell between cancerous and normal states in tissue culture.Cell Biol Int Rep 15: 595–606.
Yamada H, Omata-Yamada T, Wakabayashi-Ito N, Carter SGP, Lengyel SG (1990) Isolation of recessive (mediator−) revertants from NIH 3T3 cells transformed with a c-H-ras oncogene.Mol Cell Biol 10: 1822–1827.
Zmudzka BZ, Wilson SH (1990) Deregulation of DNA polymeraseβ by sense and antisense RNA expression in mouse 3T3 cells alters cell growth.Somatic Cell Mol Genet 16: 311–320.
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Naora, H., Xu, Z.Z., Miyahara, K. et al. Gene ecology: Acis-acting gene-to-gene interaction due to the spatial arrangement of genes in chromosomes affects neighbouring transfected c-H-ras expression. Chromosome Res 2, 171–183 (1994). https://doi.org/10.1007/BF01553317
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DOI: https://doi.org/10.1007/BF01553317