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Transcriptional regulation and transformation by Myc proteins

Nature Reviews Molecular Cell Biology volume 6, pages 635–645 (2005)Cite this article

Key Points

  • Myc genes comprise a small, multi-gene family and are implicated in the genesis of many different human tumours. Enhanced expression of Myc genes promotes unrestricted proliferation and contributes to many aspects of the tumour-cell phenotype.

  • Myc proteins are transcription factors and form obligate heterodimers with Max. They activate and repress large groups of mammalian genes by recruiting histone-modifying and chromatin-remodelling enzymes.

  • Important Myc target genes include cell-cycle regulatory genes, genes involved in protein biosynthesis and genes involved in specific metabolic pathways. Surprisingly, Myc target genes also comprise genes transcribed by RNA polymerases I and III.

  • The stability and function of Myc proteins is regulated by Ras-dependent signalling pathways.

  • Transformation by Myc proteins is inhibited by fail-safe mechanisms such as apoptosis. Precisely how Myc induces apoptosis remains unresolved, but Myc-induced genomic instability might play an important part in this process.

Abstract

Myc genes are key regulators of cell proliferation, and their deregulation contributes to the genesis of most human tumours. Recently, a wealth of data has shed new light on the biochemical functions of Myc proteins and on the mechanisms through which they function in cellular transformation.

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Figure 1: Transcriptional regulation by Myc-family proteins through E-box elements.
Figure 2: Transcriptional repression by Myc through Miz1.
Figure 3: Domains of Myc and their binding proteins.
Figure 4: Regulation of Myc function by Ras-dependent signalling pathways.
Figure 5: Regulation of transcriptional repression by Myc through Ras-dependent signalling pathways.
Figure 6: Pathways that are implicated in Myc-induced apoptosis.

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Acknowledgements

We apologize to all colleagues for the work we could not cite owing to space constraints. Work in M.E.'s laboratory is funded by the Deutsche Forschungsgemeinschaft, the European Union, the Deutsche Krebshilfe and the Thyssen Stiftung.

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Authors and Affiliations

  1. Institute for Molecular Biology and Tumour Research, University of Marburg, Emil-Mannkopff-Strasse 2, Marburg, 35033, Germany

    Sovana Adhikary & Martin Eilers

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  1. Sovana Adhikary
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  2. Martin Eilers
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Correspondence to Martin Eilers.

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DATABASES

Entrez Gene

B-Myc

c-Myc

L-Myc

N-Myc

S-Myc

Swiss-Prot

BCL2

BCL-XL

CBP

CDK4

cyclin D1

cyclin D2

DNMT3a

E2F2

GCN5

Mad4

Max

Mnt

Mxi1

p53

P300

TIP48

TIP49

TIP60

FURTHER INFORMATION

Martin Eilers' laboratory

Myc and Human Cancer Database

Glossary

LEUCINE ZIPPER

A leucine-rich protein domain that is present in a large class of dimeric transcription factors and that mediates interactions with other proteins with a similar domain. It consists of a coiled-coil of two α-helices and connects the dimerization partners.

ZINC-FINGER PROTEIN

A protein (usually a transcription factor) that contains one of several types of conserved DNA-binding motifs with conserved Cys residues. The sulphydryl groups of the Cys residues coordinate a Zn2+ ion.

HISTONE ACETYLTRANSFERASE

(HAT). An enzyme that adds acetyl groups to histones. Many HATs function as transcriptional coactivators.

HISTONE EXCHANGE FACTOR

A multiprotein complex that catalyses the replacement of canonical histones by histone variants, or the replacement of modified histone variants by unmodified histones.

CHROMATIN REMODELLING COMPLEX

A multiprotein complex that regulates the accessibility of DNA for the transcriptional machinery by ATP-dependent mobilization of nucleosomes.

E3 UBIQUITIN LIGASE

The third enzyme in a pathway that is responsible for the ubiquitylation and subsequent degradation of target proteins. E3 enzymes, which are numerous, provide platforms for binding target substrates, thereby conferring specificity to this process.

PROTEASOME

A large multisubunit protease complex that selectively degrades multi-ubiquitylated proteins. It contains a 20S component that incorporates the catalytic activity, and two regulatory 19S components.

MEDIATOR COMPLEX

A multiprotein complex that functions as a conserved interface between gene-specific regulatory proteins and the general transcriptional machinery of eukaryotes.

APC PATHWAY

Named after the adenomatous polyposis coli (APC) tumour suppressor, which regulates the level of free β-catenin by keeping β-catenin in a complex in which it is labelled for degradation. Wnt signalling through the frizzled receptor disrupts this complex and free β-catenin accumulates and can enter the nucleus to activate target genes such as Myc.

SONIC HEDGEHOG PATHWAY

Sonic hedgehog (SHH) is a secreted morphogen that derepresses the smoothened protein by binding to the patched receptor. This, in turn, activates the transcription factor GLI. The SHH pathway is essential for embryonic development.

FOXO FAMILY

A subclass of an evolutionarily highly conserved family of transcription factors that contain a so-called forkhead box.

14-3-3 PROTEINS

A family of dimeric proteins that regulate the function of substrate proteins by binding to specific phosphorylated Ser or Thr residues.

SENESCENCE

Cellular, or replicative, senescence is a process associated with ageing and longevity that leads to a limited capacity of cells to reproduce in culture.

BH3-ONLY PROTEIN

A subclass of pro-apoptotic proteins of the BCL2 family that differs from another subclass by the presence of only one of three BCL2-homology (BH) domains, BH3.

KARYOTYPE

The number, sizes and shapes of the metaphase chromosomes of a eukaryotic cell.

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Adhikary, S., Eilers, M. Transcriptional regulation and transformation by Myc proteins. Nat Rev Mol Cell Biol 6, 635–645 (2005). https://doi.org/10.1038/nrm1703

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