Abstract
MYC proto-oncogenes play a major role in various types of human tumors. The products of these genes are transcription factors that bind to specific sequences and activate the expression of target genes. Identifying these target genes and their downstream effectors is a crucial step in understanding and preventing MYC induced oncogenesis. Until now, most of the efforts to identify such genes were performed by analysing in vitro systems whose relevance to the malignant process in vivo remains unclear. We aimed at identifying genes that play a major role in the malignant process of MYC induced carcinogenesis. Thus, we analysed the expression profiles of human MYC induced tumors and compared them to similar, non-MYC tumors. Moreover, we looked for the common characteristics of different types of MYC induced tumors. We identified several genes, most of them involved in cell cycle regulation, that are over expressed in MYC induced lymphomas as well as MYC induced neuronal-like tumors. In order to determine whether MYC induced oncogenesis is similar in human and in the mouse model system, we analysed the expression of the identified genes in cells derived from transgenic mice tumors. We also present the distribution of MYC putative binding sites in the regulatory sequences of the genes identified in our analysis. This analysis pointed to two genes (E2F1 and TSC2) as candidates to be targets of Myc activity. We thus further analysed the expression of these genes in the tumor cell lines, and examined the plausibility that elements in their promoter bind the Myc protein. Our data points to several genes that may be involved in c-MYC and N-MYC induced tumors and to two genes that may be targets for MYC activity.
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Abbreviations
- BL:
-
Burkitt's lymphoma
- NB:
-
neuroblastoma
- NE:
-
neuroepithelyoma
- MYC-ER:
-
a chimeric construct of c-MYC and the estrogen receptor
- EMSA:
-
electrophoretic mobility shift assay
References
Adams MR, Sears R, Nuckolls F, Leone G, Nevins JR . 2000 Mol. Cell. Biol. 20: 3633–3639
Amati B, Dalton S, Brooks MW, Littlewood TD, Evan GI, Land H . 1992 Nature 359: 423–426
Ben-Bassat H, Polliack A, Shlomai Z, Kohn G, Hadar R, Rabinowitz R, Leizerowitz R, Matutes E, Buchier V, Brok-Simoni F, Okon E, Livni N, Schleisinger M . 1992 Leuk. Lymph. 6: 513–521
Ben-Porath I, Yanuka O, Benvenisty N . 1999 Mol. Cell. Biol. 19: 3529–3539
Ben-Yosef T, Yanuka O, Halle D, Benvenisty N . 1998 Oncogene 17: 165–171
Bishop JM . 1987 Science 235: 305–311
Blackwell TK, Kretzner L, Blackwood EM, Eisenman RN, Weintraub H . 1990 Science 250: 1149–1151
Brodeur GM, Seeger RC, Schwab M, Varmus HE, Bishop JM . 1984 Science 224: 1121–1124
Charron J, Malynn BA, Fisher P, Stewart V, Jeannotte L, Goff SP, Robertson EJ, Alt FW . 1992 Genes Dev. 6: 2248–2257
Claassen GF, Hann SR . 1999 Oncogene 18: 2925–2933
Cole MD . 1986 Annu. Rev. Genet. 20: 361–384
Coller HA, Grandori C, Tamayo P, Colbert T, Lander ES, Eisenman RN, Golub TR . 2000 Proc. Natl. Acad. Sci. USA 97: 3260–3265
Dang C . 1999 Mol. Cell. Biol. 19: 1–11
Dang CV, Lewis BC, Dolde C, Dang G, Shim H . 1997 J. Bioenerg. Biomembr. 29: 345–354
Davis AC, Wims M, Spotts GD, Hann SR, Bradley A . 1993 Genes Dev. 7: 671–682
Davis L, Halazonetis T . 1993 Oncogene 8: 125–132
Escot C, Theillet C, Lidereau R, Spyratos F, Champeme MH, Gest J, Callahan R . 1986 Proc. Natl. Acad. Sci. USA 83: 4834–4838
Evan GI, Littlewood TD . 1993 Curr. Opin. Gene Dev. 3: 44–49
Evan GI, Wyllie AH, Gilbert CS, Littlewood TD, Land H, Brooks M, Waters CM, Penn LZ, Hancock DC . 1992 Cell 69: 119–128
Facchini LM, Penn LZ . 1998 FASEB J. 12: 633–651
Freytag SO . 1988 Mol. Cell. Biol. 8: 1614–1624
Gandarillas A, Watt FM . 1997 Genes Dev. 11: 2869–2882
Gomez M, Sampson J, Whittemore V . 1999 The Tuberous Sclerosis Complex Oxford University Press: Oxford, United Kingdom
Grandori C, Eisenman RN . 1997 Trends Biochem. Sci. 22: 177–181
Guerin M, Barrois M, Terrier MJ, Spielman M, Riou G . 1988 Oncogene Res. 3: 21–31
Klein G, Giovanella B, Westman A, Stehlin JS, Mumford D . 1975 Intervirology 5: 319–334
Lassar AB, Davis RL, Wright WE, Kadesch T, Murre C, Voronova A, Baltimore D, Weintraub H . 1991 Cell 66: 305–315
Leder P, Battey J, Lenoir G, Moulding C, Murphy W, Potter H, Stewart T, Taub R . 1983 Science 222: 765–771
Leone G, Nuckolls F, Ishida S, Adams M, Sears R, Jakoi L, Miron A, Nevins JR . 2000 Mol. Cell. Biol. 20: 3626–3632
Malynn BA, de Alboran IM, O'Hagan RC, Bronson R, Davidson L, DePinho RA, Alt FW . 2000 Genes Dev. 14: 1390–1399
Marcu KB, Bossone SA, Patel AJ . 1992 Annu. Rev. Biochem. 61: 809–860
Marhin W, Chen S, Facchini L, Fornace Jr AJ, Penn L . 1997 Oncogene 14: 2825–2834
Nau MM, Brooks BJ, Battey J, Sausville E, Gazdar AF, Kirsch IR, McBride OW, Bertness V, Hollis GF, Minna JD . 1985 Nature 318: 69–73
Nesbit CE, Tersak JM, Prochownik EV . 1999 Oncogene 18: 3004–3016
O'Hagan RC, Schreiber-Agus N, Chen K, David G, Engelman JA, Schwab R, Alland L, Thomson C, Ronning DR, Sacchettini JC, Meltzer P, DePinho RA . 2000 Nature Genet. 24: 113–119
Obaya AJ, Mateyak MK, Sedivy JM . 1999 Oncogene 18: 2934–2941
Onda H, Lueck A, Marks PW, Warren HB, Kwiatkowski DJ . 1999 J. Clin. Invest. 104: 687–695
Oswald F, Lovec H, Moroy T, Lipp M . 1994 Oncogene 9: 2029–2036
Prendergast GC . 1999 Oncogene 18: 2967–2987
Prendergast GC, Ziff EB . 1992 Trends. Genet. 8: 91–96
Pulvertaft FJV . 1965 J. Clin. Path. 18: 261–266
Sadee W, Yu VC, Richards ML, Preis PN, Schwab MR, Brodsky FM, Biedler JL . 1987 Cancer Res. 47: 5207–5212
Sambrook J, Fritsch E, Maniatis T . 1989 Molecular Cloning: A Laboratory Manual second edition Cold Spring Harbor Laboratory Press
Schmidt EV . 1999 Oncogene 18: 2988–2996
Schwab M, Alitalo K, Klempnauer KH, Varmus HE, Bishop JM, Gilbert F, Brodeur G, Goldstein M, Trent J . 1983 Nature 305: 245–248
Sinn E, Muller W, Pattengale P, Tepler I, Wallace R, Leder P . 1987 Cell 49: 465–475
Soucek T, Yeung RS, Hengstschlager M . 1998 Proc. Natl. Acad. Sci. USA 95: 15653–15658
Stanton BR, Perkins AS, Tessarollo L, Sassoon DA, Parada LF . 1992 Genes Dev. 6: 2235–2247
Steinitz M, Klein G . 1975 Proc. Natl. Acad. Sci. USA 72: 3518–3520
Stewart TA, Pattengale PK, Leder P . 1984 Cell 38: 627–637
Wienecke R, Konig A, DeClue JE . 1995 J. Biol. Chem. 270: 16409–16414
Wiman KG, Clarkson B, Hayday AC, Saito H, Tonegawa S, Hayward WS . 1984 Proc. Natl. Acad. Sci 81: 6798–6802
Xiao GH, Shoarinejad F, Jin F, Golemis EA, Yeung RS . 1997 J. Biol. Chem. 272: 6097–6100
Yeger H, Baumal R, Pawlin G, Tonin P, Nissen L, Kaplinsky C, Phillips MJ . 1988 Differentiation 39: 216–227
Zimmerman KA, Yancopoulos GD, Collum RG, Smith RK, Kohl NE, Denis KA, Nau MM, Witte ON, Toran AD, Gee CE, Minna JD, Alt FW . 1986 Nature 319: 780–783
Acknowledgements
We thank Dr Uzi Motro for his help in formulating equation (1). We thank the members of our laboratory for their critical reading of the manuscript. This research was supported by grant#98-00074 from the United States–Israel Bi-national Science Foundation (BSF), Jerusalem, Israel and by a grant from the Israel Cancer Research Fund. O Schuldiner is a Clore fellow.
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Schuldiner, O., Benvenisty, N. A DNA microarray screen for genes involved in c-MYC and N-MYC oncogenesis in human tumors. Oncogene 20, 4984–4994 (2001). https://doi.org/10.1038/sj.onc.1204459
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DOI: https://doi.org/10.1038/sj.onc.1204459