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Regulation of mda-7 gene expression during human melanoma differentiation

Oncogene volume 19, pages 1362–1368 (2000)Cite this article

Abstract

Induction of irreversible growth arrest and terminal differentiation in human melanoma cells following treatment with recombinant human fibroblast interferon (IFN-β) and mezerein (MEZ) results in elevated expression of a specific melanoma differentiation associated gene, mda-7. Experiments were conducted to define the mechanism involved in the regulation of mda-7 expression in differentiating human melanoma cells. The mda-7 gene is actively transcribed in uninduced HO-1 human melanoma cells and the rate of transcription of mda-7 is not significantly enhanced by treatment with IFN-β, MEZ or IFN-β+MEZ. The high basal activity of the mda-7 promoter in uninduced melanoma cells and the absence of enhancing effect upon treatment with differentiation inducers is corroborated by transfection studies using the promoter region of mda-7 linked to a luciferase reporter gene containing the SV40 polyadenylation signal sequence. RT–PCR analysis detects the presence of low levels of mda-7 transcripts in uninduced and concomitant increases in differentiation inducer treated HO-1 cells. However, steady-state mda-7 mRNA is detected only in IFN-β+MEZ and to a lesser degree in MEZ treated cells. We show that induction of terminal differentiation of HO-1 cells with IFN-β+MEZ dramatically increases the half-life of mda-7 mRNA while treatment with cycloheximide results in detectable mda-7 mRNA in control and inducer treated cells. These observations confirm constitutive activity of the mda-7 promoter in HO-1 cells irrespective of differentiation status suggesting posttranscriptional processes as important determinants of mda-7 expression during terminal differentiation. The 3′ UTR region of mda-7 contains AU-rich elements (ARE) that contribute to rapid mda-7 mRNA turnover during proliferation and reversible differentiation, a process controlled by a labile protein factor(s). Substitution of the SV40 polyadenylation signal sequence in the luciferase reporter plasmid with the mda-7-ARE-3′-UTR renders the Luciferase message unstable when expressed in proliferating and reversibly differentiated melanoma cells. In contrast, the luciferase message is stabilized when the mda-7-ARE-3′-UTR construct is expressed in terminally differentiated HO-1 cells. These results provide compelling evidence that mda-7 expression during terminal differentiation in human melanoma cells is regulated predominantly at a posttranscriptional level.

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References

  • Aharon T and Schneider RJ . 1993 Mol Cell Biol 13: 1971–1980

  • Belasco JG and Higgins CF . 1988 Gene 72: 15–23

  • Elder PK, Schmidt LJ, Ono T and Getz MJ . 1984 Proc Natl Acad Sci USA 81: 7476–7480

  • Fisher PB, Prignoli DR, Hermo Jr H, Weinstein IB and Pestka S . 1985 Interferon Res 5: 11–22

  • Fontes AM, Ito J and Jacobs-Lorena M . 1999 Curr Top Dev Biol 44: 171–202

  • Goeddel DV, Leung DW, Dull TJ, Gross M, Lawn RM, McCandliss R, Seeburg PH, Ullrich A, Yelverton E and Gray PW . 1981 Nature 5: 20–26

  • Gopalkrishnan RV, Christiansen KA, Goldstein NI, DePinho RA and Fisher PB . 1999 Nucl Acids Res 24: 4775–4782

  • Huang F, Adelman J, Jiang H, Goldstein NI and Fisher PB . 1999a Oncogene 18: 3546–3552

  • Huang F, Adelman J, Jiang H, Goldstein NI and Fisher PB . 1999b Gene 236: 125–131

  • Huberman E and Callaham MF . 1979 Proc Natl Acad Sci USA 76: 1293–1297

  • Ishikawa M and Kerbel RS . 1989 Int J Cancer 43: 134–139

  • Jiang H, Waxman S and Fisher PB . 1993 Mol Cell Different 1: 197–214

  • Jiang H and Fisher PB . 1993 Mol Cell Different 1: 285–299

  • Jiang H, Lin J and Fisher PB . 1994 Mol Cell Different 2: 221–239

  • Jiang H, Lin JJ, Su Z-z, Goldstein NI and Fisher PB . 1995a Oncogene 11: 2477–2486

  • Jiang H, Lin J, Su Z-z, Kerbel RS, Herlyn M, Weissman RB, Welch D and Fisher PB . 1995b Oncogene 10: 1855–1864

  • Jiang H, Lin JJ, Su Z-z, Goldstein NI and Fisher PB . 1996 Proc Natl Acad Sci USA 93: 9160–9165

  • Kang D-c, LaFrance R, Su Z-z and Fisher PB . 1998a Proc Natl Acad Sci USA 95: 13788–13793

  • Kang D-c, Motwani M and Fisher PB . 1998b Int J Oncol 13: 1117–1126

  • Krowczynska A, Yenofsky R and Brawerman G . 1985 J Mol Biol 181: 231–239

  • Linial M, Gunderson N and Groudine M . 1985 Science 230: 1126–1132

  • Madireddi MT, Su Z-z, Young CSH, Goldstein NI and Fisher PB . 2000 In Cancer Gene Therapy Past Achievements and Future Challenges, Habib N ed. Plenum Publishing Company New York, NY in press

    Google Scholar 

  • Miller AD, Curran T and Verma IM . 1984 Cell 36: 51–60

  • Myer VE, Fan XC and Steitz JA . 1997 EMBO J 16: 2130–2139

  • Nedwin GE, Svedersky LP, Bringman TS, Palladino Jr MA and Goeddel DV . 1985 J Immunol 135: 2492–2497

  • Patterson A and Harris AL . 1999 Drugs Aging 14: 75–90

  • Raj NB and Pitha PM . 1981 Proc Natl Acad Sci USA 78: 7426–7430

  • Rajagopalan LE and Malter JS . 1997 Prog Nucleic Acid Res Mol Biol 56: 257–286

  • Ross J . 1996 Trends Genet 12: 171–175

  • Sachs L . 1980 Proc Natl Acad Sci USA 77: 6152–6156

  • Scott RE and Maercklein PB . 1985 Proc Natl Acad Sci USA 82: 2995–2999

  • Scott RE . 1997 Pharmacol Ther 73: 51–65

  • Shaw G and Kamen R . 1986 Cell 46: 659–667

  • Shyu AB, Belasco JG and Greenberg ME . 1991 Genes Dev 2: 221–231

  • Spicher A, Guicherit OM, Duret L, Aslanian A, Sanjines EM, Denko NC, Giaccia AJ and Blau HM . 1998 Mol Cell Biol 12: 7371–7382

  • Su Z-z, Madireddi MT, Lin JJ, Young CSH, Kitada S, Reed JC, Goldstein NI and Fisher PB . 1998 Proc Natl Acad Sci USA 95: 14400–14405

  • Tamayo P, Slonim D, Mesirov J, Zhu Q, Kitareewan S, Dimitrovsky E, Lander ES and Golub TR . 1999 Proc Natl Acad Sci USA 96: 2907–2912

  • van Straaten F, Muller R, Curran T, van Beveren C and Verma IM . 1983 Proc Natl Acad Sci USA 80: 3183–3187

  • Wada RK, Pai DS, Huang J, Yamashiro JM and Sidell N . 1997 Cancer Lett 121: 181–188

  • Waxman S, Rossi GB and Takaku F . 1991 The Status of Differentiation Therapy of Cancer, Waxman S, Rossi GB and Takaku F eds. Serono Symposia Pubs Raven Press New York

    Google Scholar 

  • Waxman S . 1995 Differentiation Therapy Waxman S ed Serono Symposium Publications Rome, Italy

    Google Scholar 

  • Wong GG, Witek JS, Temple PA, Wilkens KM, Leary AC, Luxenberg DP, Jones SS, Brown EL, Kay RM, Orr EC, Shoemaker C, Golde DW, Kaufman RJ, Hewick RM, Wang EA and Clark SC . 1985 Science 228: 810–815

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Acknowledgements

We thank Drs S Chellappan and D-c Kang for critically reviewing this manuscript. The present research was supported in part by National Cancer Institute Grant CA35675, the Samuel Waxman Cancer Research Foundation and the Chernow Endowment. MT Madireddi is supported by a fellowship award from the Army Department of Defense Initiative on Breast Cancer (DAMD17-98-1-8503). The V. Foundation, PHS RO1DK52825 and Army DOD BC 98-0148 support P Dent. PB Fisher is the Michael and Stella Chernow Urological Cancer Research Scientist.

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Authors and Affiliations

  1. Department of Urology, Herbert Irving Comprehensive Cancer Center, Columbia University, College of Physicians and Surgeons, New York, 10032, NY, USA

    Malavi T Madireddi & Paul B Fisher

  2. Department of Radiation Oncology, Medical College of Virginia, Virginia Commonwealth University, Richmond, 23298, Virginia, VA, USA

    Paul Dent

  3. Department of Neurosurgery, Herbert Irving Comprehensive Cancer Center, Columbia University, College of Physicians and Surgeons, New York, 10032, NY, USA

    Paul B Fisher

  4. Department of Pathology, Herbert Irving Comprehensive Cancer Center, Columbia University, College of Physicians and Surgeons, New York, 10032, NY, USA

    Paul B Fisher

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Madireddi, M., Dent, P. & Fisher, P. Regulation of mda-7 gene expression during human melanoma differentiation. Oncogene 19, 1362–1368 (2000). https://doi.org/10.1038/sj.onc.1203424

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