An alternative pathway for gene regulation by Myc.

K Peukert

P Staller

A Schneider

G Carmichael

F Hänel

M Eilers

Abstract

The c-Myc protein activates transcription as part of a heteromeric complex with Max. However, Myc-transformed cells are characterized by loss of expression of several genes, suggesting that Myc may also repress gene expression. Two-hybrid cloning identifies a novel POZ domain Zn finger protein (Miz-1; Myc-interacting Zn finger protein-1) that specifically interacts with Myc, but not with Max or USF. Miz-1 binds to start sites of the adenovirus major late and cyclin D1 promoters and activates transcription from both promoters. Miz-1 has a potent growth arrest function. Binding of Myc to Miz-1 requires the helix-loop-helix domain of Myc and a short amphipathic helix located in the carboxy-terminus of Miz-1. Expression of Myc inhibits transactivation, overcomes Miz-1-induced growth arrest and renders Miz-1 insoluble in vivo. These processes depend on Myc and Miz-1 association and on the integrity of the POZ domain of Miz-1, suggesting that Myc binding activates a latent inhibitory function of this domain. Fusion of a nuclear localization signal induces efficient nuclear transport of Miz-1 and impairs the ability of Myc to overcome transcriptional activation and growth arrest by Miz-1. Our data suggest a model for how gene repression by Myc may occur in vivo.

Full Text

The Full Text of this article is available as a PDF (1.0M).

Selected References

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

Craig RW, Buchan HL, Civin CI, Kastan MB. Altered cytoplasmic/nuclear distribution of the c-myc protein in differentiating ML-1 human myeloid leukemia cells. Cell Growth Differ. 1993 May;4(5):349–357. [PubMed] [Google Scholar]
Desbarats L, Gaubatz S, Eilers M. Discrimination between different E-box-binding proteins at an endogenous target gene of c-myc. Genes Dev. 1996 Feb 15;10(4):447–460. [PubMed] [Google Scholar]
Dhordain P, Albagli O, Ansieau S, Koken MH, Deweindt C, Quief S, Lantoine D, Leutz A, Kerckaert JP, Leprince D. The BTB/POZ domain targets the LAZ3/BCL6 oncoprotein to nuclear dots and mediates homomerisation in vivo. Oncogene. 1995 Dec 21;11(12):2689–2697. [PubMed] [Google Scholar]
Du H, Roy AL, Roeder RG. Human transcription factor USF stimulates transcription through the initiator elements of the HIV-1 and the Ad-ML promoters. EMBO J. 1993 Feb;12(2):501–511.[PMC free article] [PubMed] [Google Scholar]
Eilers M, Picard D, Yamamoto KR, Bishop JM. Chimaeras of myc oncoprotein and steroid receptors cause hormone-dependent transformation of cells. Nature. 1989 Jul 6;340(6228):66–68. [PubMed] [Google Scholar]
Evan GI, Hancock DC. Studies on the interaction of the human c-myc protein with cell nuclei: p62c-myc as a member of a discrete subset of nuclear proteins. Cell. 1985 Nov;43(1):253–261. [PubMed] [Google Scholar]
Facchini LM, Chen S, Marhin WW, Lear JN, Penn LZ. The Myc negative autoregulation mechanism requires Myc-Max association and involves the c-myc P2 minimal promoter. Mol Cell Biol. 1997 Jan;17(1):100–114.[PMC free article] [PubMed] [Google Scholar]
Ferré-D'Amaré AR, Prendergast GC, Ziff EB, Burley SK. Recognition by Max of its cognate DNA through a dimeric b/HLH/Z domain. Nature. 1993 May 6;363(6424):38–45. [PubMed] [Google Scholar]
Fields S, Song O. A novel genetic system to detect protein-protein interactions. Nature. 1989 Jul 20;340(6230):245–246. [PubMed] [Google Scholar]
Freytag SO, Geddes TJ. Reciprocal regulation of adipogenesis by Myc and C/EBP alpha. Science. 1992 Apr 17;256(5055):379–382. [PubMed] [Google Scholar]
Galaktionov K, Lee AK, Eckstein J, Draetta G, Meckler J, Loda M, Beach D. CDC25 phosphatases as potential human oncogenes. Science. 1995 Sep 15;269(5230):1575–1577. [PubMed] [Google Scholar]
Henriksson M, Lüscher B. Proteins of the Myc network: essential regulators of cell growth and differentiation. Adv Cancer Res. 1996;68:109–182. [PubMed] [Google Scholar]
Herber B, Truss M, Beato M, Müller R. Inducible regulatory elements in the human cyclin D1 promoter. Oncogene. 1994 Apr;9(4):1295–1304. [PubMed] [Google Scholar]
Hurlin PJ, Quéva C, Koskinen PJ, Steingrímsson E, Ayer DE, Copeland NG, Jenkins NA, Eisenman RN. Mad3 and Mad4: novel Max-interacting transcriptional repressors that suppress c-myc dependent transformation and are expressed during neural and epidermal differentiation. EMBO J. 1996 Apr 15;15(8):2030–2030.[PMC free article] [PubMed] [Google Scholar]
Albagli O, Dhordain P, Deweindt C, Lecocq G, Leprince D. The BTB/POZ domain: a new protein-protein interaction motif common to DNA- and actin-binding proteins. Cell Growth Differ. 1995 Sep;6(9):1193–1198. [PubMed] [Google Scholar]
Inghirami G, Grignani F, Sternas L, Lombardi L, Knowles DM, Dalla-Favera R. Down-regulation of LFA-1 adhesion receptors by C-myc oncogene in human B lymphoblastoid cells. Science. 1990 Nov 2;250(4981):682–686. [PubMed] [Google Scholar]
Alexandrova N, Niklinski J, Bliskovsky V, Otterson GA, Blake M, Kaye FJ, Zajac-Kaye M. The N-terminal domain of c-Myc associates with alpha-tubulin and microtubules in vivo and in vitro. Mol Cell Biol. 1995 Sep;15(9):5188–5195.[PMC free article] [PubMed] [Google Scholar]
Amati B, Brooks MW, Levy N, Littlewood TD, Evan GI, Land H. Oncogenic activity of the c-Myc protein requires dimerization with Max. Cell. 1993 Jan 29;72(2):233–245. [PubMed] [Google Scholar]
Judware R, Culp LA. Over-expression of transfected N-myc oncogene in human SKNSH neuroblastoma cells down-regulates expression of beta 1 integrin subunit. Oncogene. 1995 Dec 21;11(12):2599–2607. [PubMed] [Google Scholar]
Auvinen M, Paasinen A, Andersson LC, Hölttä E. Ornithine decarboxylase activity is critical for cell transformation. Nature. 1992 Nov 26;360(6402):355–358. [PubMed] [Google Scholar]
Kretzner L, Blackwood EM, Eisenman RN. Myc and Max proteins possess distinct transcriptional activities. Nature. 1992 Oct 1;359(6394):426–429. [PubMed] [Google Scholar]
Li LH, Nerlov C, Prendergast G, MacGregor D, Ziff EB. c-Myc represses transcription in vivo by a novel mechanism dependent on the initiator element and Myc box II. EMBO J. 1994 Sep 1;13(17):4070–4079.[PMC free article] [PubMed] [Google Scholar]
Berberich SJ, Cole MD. Casein kinase II inhibits the DNA-binding activity of Max homodimers but not Myc/Max heterodimers. Genes Dev. 1992 Feb;6(2):166–176. [PubMed] [Google Scholar]
Lindeman GJ, Gaubatz S, Livingston DM, Ginsberg D. The subcellular localization of E2F-4 is cell-cycle dependent. Proc Natl Acad Sci U S A. 1997 May 13;94(10):5095–5100.[PMC free article] [PubMed] [Google Scholar]
Blackwell TK, Kretzner L, Blackwood EM, Eisenman RN, Weintraub H. Sequence-specific DNA binding by the c-Myc protein. Science. 1990 Nov 23;250(4984):1149–1151. [PubMed] [Google Scholar]
Mink S, Mutschler B, Weiskirchen R, Bister K, Klempnauer KH. A novel function for Myc: inhibition of C/EBP-dependent gene activation. Proc Natl Acad Sci U S A. 1996 Jun 25;93(13):6635–6640.[PMC free article] [PubMed] [Google Scholar]
Morgenstern JP, Land H. Advanced mammalian gene transfer: high titre retroviral vectors with multiple drug selection markers and a complementary helper-free packaging cell line. Nucleic Acids Res. 1990 Jun 25;18(12):3587–3596.[PMC free article] [PubMed] [Google Scholar]
Nordeen SK. Luciferase reporter gene vectors for analysis of promoters and enhancers. Biotechniques. 1988 May;6(5):454–458. [PubMed] [Google Scholar]
Pagano M, Theodoras AM, Tam SW, Draetta GF. Cyclin D1-mediated inhibition of repair and replicative DNA synthesis in human fibroblasts. Genes Dev. 1994 Jul 15;8(14):1627–1639. [PubMed] [Google Scholar]
Pear WS, Nolan GP, Scott ML, Baltimore D. Production of high-titer helper-free retroviruses by transient transfection. Proc Natl Acad Sci U S A. 1993 Sep 15;90(18):8392–8396.[PMC free article] [PubMed] [Google Scholar]
Phelps WC, Yee CL, Münger K, Howley PM. The human papillomavirus type 16 E7 gene encodes transactivation and transformation functions similar to those of adenovirus E1A. Cell. 1988 May 20;53(4):539–547. [PubMed] [Google Scholar]
Philipp A, Schneider A, Väsrik I, Finke K, Xiong Y, Beach D, Alitalo K, Eilers M. Repression of cyclin D1: a novel function of MYC. Mol Cell Biol. 1994 Jun;14(6):4032–4043.[PMC free article] [PubMed] [Google Scholar]
Picard D, Salser SJ, Yamamoto KR. A movable and regulable inactivation function within the steroid binding domain of the glucocorticoid receptor. Cell. 1988 Sep 23;54(7):1073–1080. [PubMed] [Google Scholar]
Prendergast GC, Ziff EB. Methylation-sensitive sequence-specific DNA binding by the c-Myc basic region. Science. 1991 Jan 11;251(4990):186–189. [PubMed] [Google Scholar]
Prendergast GC, Lawe D, Ziff EB. Association of Myn, the murine homolog of max, with c-Myc stimulates methylation-sensitive DNA binding and ras cotransformation. Cell. 1991 May 3;65(3):395–407. [PubMed] [Google Scholar]
Roy AL, Carruthers C, Gutjahr T, Roeder RG. Direct role for Myc in transcription initiation mediated by interactions with TFII-I. Nature. 1993 Sep 23;365(6444):359–361. [PubMed] [Google Scholar]
Rudolph B, Saffrich R, Zwicker J, Henglein B, Müller R, Ansorge W, Eilers M. Activation of cyclin-dependent kinases by Myc mediates induction of cyclin A, but not apoptosis. EMBO J. 1996 Jun 17;15(12):3065–3076.[PMC free article] [PubMed] [Google Scholar]
Schulz TC, Hopwood B, Rathjen PD, Wells JR. An unusual arrangement of 13 zinc fingers in the vertebrate gene Z13. Biochem J. 1995 Oct 1;311(Pt 1):219–224.[PMC free article] [PubMed] [Google Scholar]
Schwab M, Praml C, Amler LC. Genomic instability in 1p and human malignancies. Genes Chromosomes Cancer. 1996 Aug;16(4):211–229. [PubMed] [Google Scholar]
Shibuya H, Yoneyama M, Ninomiya-Tsuji J, Matsumoto K, Taniguchi T. IL-2 and EGF receptors stimulate the hematopoietic cell cycle via different signaling pathways: demonstration of a novel role for c-myc. Cell. 1992 Jul 10;70(1):57–67. [PubMed] [Google Scholar]
Shrivastava A, Saleque S, Kalpana GV, Artandi S, Goff SP, Calame K. Inhibition of transcriptional regulator Yin-Yang-1 by association with c-Myc. Science. 1993 Dec 17;262(5141):1889–1892. [PubMed] [Google Scholar]
Stone J, de Lange T, Ramsay G, Jakobovits E, Bishop JM, Varmus H, Lee W. Definition of regions in human c-myc that are involved in transformation and nuclear localization. Mol Cell Biol. 1987 May;7(5):1697–1709.[PMC free article] [PubMed] [Google Scholar]
Tommerup N, Vissing H. Isolation and fine mapping of 16 novel human zinc finger-encoding cDNAs identify putative candidate genes for developmental and malignant disorders. Genomics. 1995 May 20;27(2):259–264. [PubMed] [Google Scholar]
Versteeg R, Noordermeer IA, Krüse-Wolters M, Ruiter DJ, Schrier PI. c-myc down-regulates class I HLA expression in human melanomas. EMBO J. 1988 Apr;7(4):1023–1029.[PMC free article] [PubMed] [Google Scholar]
Wakamatsu Y, Watanabe Y, Shimono A, Kondoh H. Transition of localization of the N-Myc protein from nucleus to cytoplasm in differentiating neurons. Neuron. 1993 Jan;10(1):1–9. [PubMed] [Google Scholar]
Yang BS, Geddes TJ, Pogulis RJ, de Crombrugghe B, Freytag SO. Transcriptional suppression of cellular gene expression by c-Myc. Mol Cell Biol. 1991 Apr;11(4):2291–2295.[PMC free article] [PubMed] [Google Scholar]
Zervos AS, Gyuris J, Brent R. Mxi1, a protein that specifically interacts with Max to bind Myc-Max recognition sites. Cell. 1993 Jan 29;72(2):223–232. [PubMed] [Google Scholar]

Hans-Knöll-Institut für Naturstoff-Forschung, Department of Cell and Molecular Biology, Beutenbergstrasse 11, 07745 Jena, Germany.

Abstract

Full Text

Selected References