Cell Density and Paradoxical Transcriptional Properties of C-Myc and Max in Cultured Mouse Fibroblasts

Overview

Journal J Clin Invest

Specialty General Medicine

Date 1995 Feb 1

PMID 7860774

Citations 10

Authors

L A Lee

L M Resar

C V Dang

Affiliations

Soon will be listed here.

Abstract

Deregulated expression of the c-Myc oncoprotein occurs in several human malignancies. The c-Myc protein behaves as a transcription factor, and undoubtedly its role in carcinogenesis involves its ability to affect the expression of genes involved in cell growth. c-Myc has been reported to both activate and repress transcription in transient transfection experiments using reporter constructs bearing multiple copies of the c-Myc binding site, CAC (G/A) TG. We investigated these apparently paradoxical effects of c-Myc by determining if they arose from differences in the cell proliferation states of transfected cells. We found that endogenous c-Myc protein levels vary inversely with the degree of cell confluency, such that at low cell confluency, where endogenous levels of c-Myc are high and presumably endogenous levels of Max are limiting, exogenous c-Myc fails to affect basal transcription. In cells at high cell confluency, in which endogenous c-Myc levels are low, exogenous c-Myc augments transactivation by titrating the relative excess endogenous Max. These observations suggest that the apparently paradoxical behavior of c-Myc in transfection experiments is partially dependent on ambient cellular levels of c-Myc.

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References

Shi Y, Glynn J, Guilbert L, Cotter T, Bissonnette R, Green D . Role for c-myc in activation-induced apoptotic cell death in T cell hybridomas. Science. 1992; 257(5067):212-4. DOI: 10.1126/science.1378649. View

Kato G, Dang C . Function of the c-Myc oncoprotein. FASEB J. 1992; 6(12):3065-72. DOI: 10.1096/fasebj.6.12.1521738. View

Kretzner L, Blackwood E, Eisenman R . Myc and Max proteins possess distinct transcriptional activities. Nature. 1992; 359(6394):426-9. DOI: 10.1038/359426a0. View

Reddy C, Dasgupta P, Saikumar P, Dudek H, Rauscher 3rd F, Reddy E . Mutational analysis of Max: role of basic, helix-loop-helix/leucine zipper domains in DNA binding, dimerization and regulation of Myc-mediated transcriptional activation. Oncogene. 1992; 7(10):2085-92. View

Van Antwerp M, Chen D, Chang C, Prochownik E . A point mutation in the MyoD basic domain imparts c-Myc-like properties. Proc Natl Acad Sci U S A. 1992; 89(19):9010-4. PMC: 50054. DOI: 10.1073/pnas.89.19.9010. View

Auvinen M, Paasinen A, Andersson L, Holtta E . Ornithine decarboxylase activity is critical for cell transformation. Nature. 1992; 360(6402):355-8. DOI: 10.1038/360355a0. View

Ayer D, Kretzner L, Eisenman R . Mad: a heterodimeric partner for Max that antagonizes Myc transcriptional activity. Cell. 1993; 72(2):211-22. DOI: 10.1016/0092-8674(93)90661-9. View

Zervos A, Gyuris J, Brent R . Mxi1, a protein that specifically interacts with Max to bind Myc-Max recognition sites. Cell. 1993; 72(2):223-32. DOI: 10.1016/0092-8674(93)90662-a. View

Amati B, Brooks M, Levy N, Littlewood T, Evan G, Land H . Oncogenic activity of the c-Myc protein requires dimerization with Max. Cell. 1993; 72(2):233-45. DOI: 10.1016/0092-8674(93)90663-b. View

10.

Jansen-Durr P, Meichle A, Steiner P, Pagano M, Finke K, Botz J . Differential modulation of cyclin gene expression by MYC. Proc Natl Acad Sci U S A. 1993; 90(8):3685-9. PMC: 46366. DOI: 10.1073/pnas.90.8.3685. View

11.

Packham G, Cleveland J . The ornithine decarboxylase gene is a transcriptional target of c-Myc. Proc Natl Acad Sci U S A. 1993; 90(16):7804-8. PMC: 47231. DOI: 10.1073/pnas.90.16.7804. View

12.

Roy A, Carruthers C, Gutjahr T, Roeder R . Direct role for Myc in transcription initiation mediated by interactions with TFII-I. Nature. 1993; 365(6444):359-61. DOI: 10.1038/365359a0. View

13.

Ayer D, Eisenman R . A switch from Myc:Max to Mad:Max heterocomplexes accompanies monocyte/macrophage differentiation. Genes Dev. 1993; 7(11):2110-9. DOI: 10.1101/gad.7.11.2110. View

14.

Larsson L, Pettersson M, Oberg F, Nilsson K, Luscher B . Expression of mad, mxi1, max and c-myc during induced differentiation of hematopoietic cells: opposite regulation of mad and c-myc. Oncogene. 1994; 9(4):1247-52. View

15.

Philipp A, Schneider A, Vasrik I, Finke K, Xiong Y, Beach D . Repression of cyclin D1: a novel function of MYC. Mol Cell Biol. 1994; 14(6):4032-43. PMC: 358769. DOI: 10.1128/mcb.14.6.4032-4043.1994. View

16.

Li L, Nerlov C, Prendergast G, MacGregor D, Ziff E . c-Myc represses transcription in vivo by a novel mechanism dependent on the initiator element and Myc box II. EMBO J. 1994; 13(17):4070-9. PMC: 395328. DOI: 10.1002/j.1460-2075.1994.tb06724.x. View

17.

Hirt B . Selective extraction of polyoma DNA from infected mouse cell cultures. J Mol Biol. 1967; 26(2):365-9. DOI: 10.1016/0022-2836(67)90307-5. View

18.

Land H, Parada L, Weinberg R . Tumorigenic conversion of primary embryo fibroblasts requires at least two cooperating oncogenes. Nature. 1983; 304(5927):596-602. DOI: 10.1038/304596a0. View

19.

Zimmerman K, Yancopoulos G, Collum R, Smith R, Kohl N, Denis K . Differential expression of myc family genes during murine development. Nature. 1986; 319(6056):780-3. DOI: 10.1038/319780a0. View

20.

Lee W, Schwab M, Westaway D, Varmus H . Augmented expression of normal c-myc is sufficient for cotransformation of rat embryo cells with a mutant ras gene. Mol Cell Biol. 1985; 5(12):3345-56. PMC: 369162. DOI: 10.1128/mcb.5.12.3345-3356.1985. View