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  • Original Paper
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Mlx, a new Max-like bHLHZip family member: the center stage of a novel transcription factors regulatory pathway?

Abstract

The Myc proto-oncogene family members have been identified as the cellular homologs of the transforming oncogene of avian retroviruses. They encode central regulators of mammalian cell proliferation and apoptosis, and they associate with the bHLHZip protein Max to bind specific DNA sequences and regulate the expression of genes important for cell cycle progression. The other family members, Mad1, Mxi1, Mad3, Mad4 and Rox (Mnt) antagonize their activities. The Mads and Rox compete with Myc in heterodimerizing with Max and in binding to the same specific target sequences. These Mads:Max and Rox:Max dimers repress transcription through binding to the mSIN3 corepressor protein and by tethering histone deacetylase-containing complexes to the DNA. In a screen for Rox interactors we isolated Mlx, a bHLHZip protein previously identified in a screen for Mad1 interactors. In the present work we extend the known dimerization partners of Mlx by demonstrating its ability to interact with Rox. Moreover, we show that contrary to previous reports Mlx is able to homodimerize and to bind E-box sequences at low concentration levels. The possible role of Mlx in an emerging regulatory pathway and acting parallel to the Max driven network is discussed.

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References

  • Aita VM, Liang XH, Murty VV, Pincus DL, Yu W, Cayanis E, Kalachikov S, Gilliam TC and Levine B. . 1999 Genomics 59: 59–65.

  • Alland L, Muhle R, Hou Jr H, Potes J, Chin L, Schreiber Agus N and DePinho RA. . 1997 Nature 387: 49–55.

  • Amati B, Dalton S, Brooks MW, Littlewood TD, Evan GI and Land H. . 1992 Nature 359: 423–426.

  • Amati B and Land H. . 1994 Curr. Opin. Genet. Dev. 4: 102–108.

  • Armelin HA, Armelin MCS, Kelly K, Stewart T, Leder P, Cochran BH and Stiles CD. . 1984 Nature 310: 655–660.

  • Ayer DE, Kretzner L and Eisenman RN. . 1993 Cell 72: 211–222.

  • Ayer DE, Lawrence QA and Eisenman RN. . 1995 Cell 80: 767–776.

  • Beckmann H, Su LK and Kadesch T. . 1990 Genes Dev. 4: 167–179.

  • Berberich SJ and Cole MD. . 1992 Genes Dev. 6: 166–176.

  • Billin AN, Eilers AL, Queva C and Ayer DE. . 1999 J. Biol. Chem. 274: 36344–36350.

  • Bjerknes M and Cheng H. . 1996 Gene 181: 7–11.

  • Blackwell TK, Huang J, Ma A, Kretzner L, Alt FW, Eisenman RN and Weintraub H. . 1993 Mol. Cell. Biol. 13: 5216–5224.

  • Blackwood EM and Eisenman RN. . 1991 Science 251: 1211–1217.

  • Blackwood EM, Luscher B and Eisenman RN. . 1992 Genes Dev. 6: 71–80.

  • Bush A, Mateyak M, Dugan K, Obaya A, Adachi S, Sedivy J and Cole M. . 1998 Genes Dev. 12: 3797–3802.

  • Campisi J, Gray HE, Pardee AB, Dean M and Sonenshein G. . 1984 Cell 36: 241–247.

  • Chomczynsky P and Sacchi N. . 1987 Analytical Chemistry 162: 156–159.

  • Claassen GF and Hann SR. . 1999 Oncogene 18: 2925–2933.

  • Cole MD and McMahon SB. . 1999 Oncogene 18: 2916–2924.

  • Dang CV. . 1999 Mol. Cell Biol. 19: 1–11.

  • Eagle LR, Yin X, Brothman AR, Williams BJ, Atkin NB and Prochownik EV. . 1995 Nat. Genet. 9: 249–255.

  • Eilers M. . 1999 Mol. Cells 9: 1–6.

  • Fisher DE, Carr CS, Parent LA and Sharp PA. . 1991 Genes Dev. 5: 2342–2352.

  • FitzGerald MJ, Arsura M, Bellas RE, Yang W, Wu M, Chin L, Mann KK, DePinho RA and Sonenshein GE. . 1999 Oncogene 18: 2489–2498.

  • Friedman LS, Ostermeyer EA, Lynch ED, Szabo CI, Anderson LA, Dowd P, Lee MK, Rowell SE, Boyd J and King MC. . 1994 Cancer Res. 54: 6374–6382.

  • Friedman LS, Ostermeyer EA, Lynch ED, Welcsh P, Szabo CI, Meza JE, Anderson LA, Dowd P, Lee MK and Rowell SE. . 1995 Genomics 25: 256–263.

  • Futreal PA, Liu Q, Shattuck Eidens D, Cochran C, Harshman K, Tavtigian S, Bennett LM, Haugen Strano A, Swensen J and Miki Y. . 1994 Science 266: 120–122.

  • Gallant P, Shiio Y, Cheng PF, Parkhurst SM and Eisenman RN. . 1996 Science 274: 1523–1527.

  • Gregor PD, Sawadogo M and Roeder RG. . 1990 Genes Dev. 4: 1730–1740.

  • Gu W, Cechova K, Tassi V and Dalla Favera R. . 1993 Proc. Natl. Acad. Sci. USA 90: 2935–2939.

  • Gupta K, Anand G, Yin X, Grove L and Prochownik EV. . 1998 Oncogene 16: 1149–1159.

  • Gyuris J, Golemis E, Chertkov H and Brent R. . 1993 Cell 75: 791–803.

  • Hassig CA, Fleischer TC, Billin AN, Schreiber SL and Ayer DE. . 1997 Cell 89: 341–347.

  • Heinzel T, Lavinsky RM, Mullen TM, Soderstrom M, Laherty CD, Torchia J, Yang WM, Brard G, Ngo SD, Davie JR, Seto E, Eisenman RN, Rose DW, Glass CK and Rosenfeld MG. . 1997 Nature 387: 43–48.

  • Hemesath TJ, Steingrimsson E, McGill G, Hansen MJ, Vaught J, Hodgkinson CA, Arnheiter H, Copeland NG, Jenkins NA and Fisher DE. . 1994 Genes Dev. 8: 2770–2780.

  • Hesketh R. . 1997 The Oncogene and Tumour Suppressor Gene FactsBook Second Edition Academic Press, Harcourt Brace and Company, San Diego, London, Boston, New York, Sydney, Toronto. pp 1–549.

  • Hodgkinson CA. . 1993 Cell 74: 395–404.

  • Hopewell R and Ziff EB. . 1995 Mol. Cell. Biol. 15: 3470–3478.

  • Hurlin PJ, Foley KP, Ayer DE, Eisenman RN, Hanahan D and Arbeit JM. . 1995a Oncogene 11: 2487–2501.

  • Hurlin PJ, Queva C and Eisenman RN. . 1997 Genes Dev. 11: 44–58.

  • Hurlin PJ, Queva C, Koskinen PJ, Steingrimsson E, Ayer DE, Copeland NG, Jenkins NA and Eisenman RN. . 1995b EMBO J. 15: 2030.

  • Kasten MM, Ayer DE and Stillman DJ. . 1996 Mol. Cell. Biol. 16: 4215–4221.

  • Kasten MM, Dorland S and Stillman DJ. . 1997 Mol. Cell. Biol. 17: 4852–4858.

  • Kelly K, Cochran BH, Stiles CD and Leder P. . 1983 Cell 35: 603–610.

  • Kozak M. . 1984 Nucleic Acids Res. 12: 857–873.

  • Kretzner L, Blackwood EM and Eisenman RN. . 1992 Nature 359: 426–429.

  • Laherty CD, Yang WM, Sun JM, Davie JR, Seto E and Eisenman RN. . 1997 Cell 89: 349–356.

  • Larsson LG, Pettersson M, Oberg F, Nilsson K and Luscher B. . 1994 Oncogene 9: 1247–1252.

  • Lee NH, Weinstock KG, Kirkness EF, Earle Hughes JA, Fuldner RA, Marmaros S, Glodek A, Gocayne JD, Adams MD, Kerlavage AR, Fraser CM and Venter JC. . 1995 Proc. Natl. Acad. Sci. USA 92: 8303–8307.

  • Li LH, Nerlov C, Prendergast G, MacGregor D and Ziff EB. . 1994 EMBO J. 13: 4070–4079.

  • Li XJ, Wang DY, Zhu Y, Guo RJ, Wang XD, Lubomir K, Mukai K, Sasaki H, Yoshida H, Oka T, Machinami R, Shinmura K, Tanaka M and Sugimura H. . 1999 Jpn. J. Cancer Res. 90: 740–746.

  • Ló Nigro C, Venesio T, Reymond A, Meroni G, Alberici P, Cainarca S, Enrico F, Stack M, Ledbetter DH, Liscia DS, Ballabio A and Carrozzo R. . 1998 Genomics 49: 275–282.

  • Makela TP, Koskinen PJ, Vastrik I and Alitalo K. . 1992 Science 256: 373–377.

  • Meroni G, Reymond A, Alcalay M, Borsani G, Tanigami A, Tonlorenzi R, Ló Nigro C, Messali S, Zollo M, Ledbetter DH, Brent R, Ballabio A and Carrozzo R. . 1997 EMBO J. 16: 2892–2906.

  • Miki Y. . 1994 Science 266: 66–71.

  • Nagy L, Kao HY, Chakravarti D, Lin RJ, Hassig CA, Ayer DE, Schreiber SL and Evans RM. . 1997 Cell 89: 373–380.

  • Nesbit CE, Tersak JM and Prochownik EV. . 1999 Oncogene 18: 3004–3016.

  • Nigg EA. . 1997 Nature 386: 779–787.

  • Peters MA and Taparowsky EJ. . 1998 Crit. Rev. Eukaryot. Gene Expr. 8: 277–296.

  • Peukert K, Staller P, Schneider A, Carmichael G, Hanel F and Eilers M. . 1997 EMBO J. 16: 5672–5686.

  • Prendergast GC, Lawe D and Ziff EB. . 1991 Cell 65: 395–407.

  • Prochownik EV and VanAntwerp ME. . 1993 Proc. Natl. Acad. Sci. USA 90: 960–964.

  • Queva C, Hurlin PJ, Foley KP and Eisenman RN. . 1998 Oncogene 16: 967–977.

  • Reymond A and Brent R. . 1995 Oncogene 11: 1173–1178.

  • Reymond A, Volorio S, Merla G, Al Maghttheh M, Zuffardi O, Bulfone A, Ballabio A and Zollo M. . 1999 Oncogene 18: 7244–7252.

  • Riddle RD, Johnson RL, Laufer E and Tabin C. . 1993 Cell 75: 1401–1416.

  • Roussel MF, Ashmun RA, Sherr CJ, Eisenman RN and Ayer DE. . 1996 Mol. Cell. Biol. 16: 2796–2801.

  • Ryan KM and Birnie GD. . 1997 Biochem. J. 325: 79–85.

  • Schreiber Agus N, Chin L, Chen K, Torres R, Rao G, Guida P, Skoultchi AI and DePinho RA. . 1995 Cell 80: 777–786.

  • Schreiber Agus N, Meng Y, Hoang T, Hou Jr H, Chen K, Greenberg R, Cordon Cardo C, Lee HW and DePinho RA. . 1998 Nature 393: 483–487.

  • Schreiber Agus N, Stein D, Chen K, Goltz JS, Stevens L and DePinho RA. . 1997 Proc. Natl Acad. Sci. USA 94: 1235–1240.

  • Shrivastava A, Saleque S, Kalpana GV, Artandi S, Goff SP and Calame K. . 1993 Science 262: 1889–1892.

  • Sirito M, Lin Q, Maity T and Sawadogo M. . 1994 Nucleic Acids Res. 22: 427–433.

  • Sirito M, Walker S, Lin Q, Kozlowski MT, Klein WH and Sawadogo M. . 1992 Gene Expr. 2: 231–240.

  • Tangir J, Muto MG, Berkowitz RS, Welch WR, Bell DA and Mok SC. . 1996 Oncogene 12: 735–740.

  • Taunton J, Hassig CA and Schreiber SL. . 1996 Science 272: 408–411.

  • Vastrik I, Koskinen PJ, Alitalo R and Makela TP. . 1993 Oncogene 8: 503–507.

  • Vogelstein B and Kinzler KW. . 1994 Cell 79: 1–3.

  • Walker CW, Boom JD and Marsh AG. . 1992 Oncogene 7: 2007–2012.

  • Yin X, Grove L and Prochownik EV. . 1998 Oncogene 16: 2629–2637.

  • Yuan J, Tirabassi RS, Bush AB and Cole MD. . 1998 Oncogene 17: 1109–1118.

  • Zervos AS, Gyuris J and Brent R. . 1993 Cell 72: 223–232.

  • Zhang H, Fan S and Prochownik EV. . 1997a J. Biol. Chem. 272: 17416–17424.

  • Zhang Y, Iratni R, Erdjument Bromage H, Tempst P and Reinberg D. . 1997b Cell 89: 357–364.

  • Zhao GQ, Zhao Q, Zhou X, Mattei MG and de Crombrugghe B. . 1993 Mol. Cell. Biol. 13: 4505–4512.

  • Zhao Z, Yazdani A, Shen Y, Sun Z, Bailey J, Caskey CT and Lee CC. . 1996 Mamm. Genome 7: 686–690.

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Acknowledgements

We thank Pierre Colas, Fabrizia Urbinati and Elena Zanaria for their helpful suggestions and/or critical reading of the manuscript. We would like to thank Maria Teresa Bassi, Claudio Gattuso, Cristina Mocchetti, Gyorgy Simon, Sara Volorio and Massimo Zollo for core assistance and Anne Simon and Melissa Smith for help in preparation of the manuscript. We are grateful to DE Ayer, G Borsani, S Cainarca, SC Chandrasekharappa, BA Cohen, CV Dang, C Dargemont, L Desbarats, M Eilers, RN Eisenman, RL Finley Jr, RA DePinho, PJ Hurlin, RE Kingston, H Land, J Lopez, V Marigo, EV Prochownik, N Schreiber-Agus, V Zappavigna and AS Zervos for technical suggestions and reagents. This work was supported by a Biomed2 European Community grant to G Meroni, a ‘Fondazione Italiana per la Ricerca sul Cancro’ fellowship to G Merla, and by a Swiss National Science Foundation fellowship and a Telethon Foundation fellowship to A Reymond. Please note that part of this work was performed while R Brent and A Reymond were working at the Department of Molecular Biology, Massachusetts General Hospital and Department of Genetics, Harvard Medical School, Boston, MA, USA.

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Meroni, G., Cairo, S., Merla, G. et al. Mlx, a new Max-like bHLHZip family member: the center stage of a novel transcription factors regulatory pathway?. Oncogene 19, 3266–3277 (2000). https://doi.org/10.1038/sj.onc.1203634

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