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MAPK-regulated transcription: a continuously variable gene switch?

Nature Reviews Molecular Cell Biology volume 3, pages 30–40 (2002)Cite this article

Abstract

Switching mechanisms that control genes could be viewed either as stable binary switches, in which genes exist in 'on' or 'off' states; or as quantitative rheostat-like switches, in which the rate of transcription is continuously variable and coupled directly to the strength of intracellular signalling events. Here, we discuss the biological need for quantitative gene regulation and, using mitogen-activated protein kinase (MAPK)-controlled transcription as a model, assess the evidence for its existence and postulate mechanisms by which it might occur.

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Figure 1: Concentration-dependent specification of cell fate by diffusion of morphogen.
Figure 2: Differential expression of IE genes in response to various stimuli.
Figure 3: Transcription-factor binding sites involved in IE gene expression.
Figure 4: Mammalian MAPK cascades.

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Acknowledgements

We remember Professor Nigel H. K. Holder (1953–1998), Director of the Developmental Biology Research Centre (DBRC), Randall Institute, King's College London. This review benefits from enjoyable and stimulating discussions with him and with other colleagues at the DBRC and at various DBRC retreats. We thank members of our laboratory, especially E. Cano, for their contributions. C. A. H. is funded by the Cancer Research Campaign. We apologize for omitting to cite much related literature due to the breadth of subject matter covered here and space constraints.

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Authors and Affiliations

  1. Department of Biochemistry, Nuclear Signalling Laboratory, University of Oxford, South Parks Road, Oxford, OX1 3QU, UK

    Catherine A. Hazzalin & Louis C. Mahadevan

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  1. Catherine A. Hazzalin
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Correspondence to Louis C. Mahadevan.

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DATABASES

LocusLink:

bFGF

EGF

ERK1

ERK2

PCAF

 Swiss-Prot:

ATF-2

CBP

c-fos

c-jun

CREB

Elk-1

fosB

HMG-14

junB

junD

p300

related serum response factor (RSRF)/myocyte enhancer factor (MEF)

RSK2

SRF

Glossary

TISSUE-SPECIFIC GENES

Genes that encode proteins that are required only in certain types of cells.

HOUSEKEEPING GENES

Genes that are expressed in almost every cell, as they encode proteins that are essential for the viability of the cell.

STOCHASTIC

Probabilistic; governed by chance.

IMMEDIATE-EARLY GENES

Genes that are induced rapidly and transiently without a need for new protein synthesis. Many immediate-early genes, such as Fos, control the transcription of other genes, and thereby alter the genetic programme in the nucleus.

JAK/STAT SIGNALLING SYSTEM

There are four Janus kinases (JAKs) (JAK1, JAK2, JAK3 and TYK2), which are activated by growth factors, cytokines and interferons and induce the phosphorylation of the cytokine/interferon receptors and other cellular substrates, including signal transducers and activators of transcription (STAT) proteins. Phosphorylation induces STAT to dimerize and translocate into the nucleus, where they function as transcription factors.

NUCLEOSOME

The basic structural subunit of chromatin, which consists of ∼150 base pairs of DNA and an octamer of histones.

ACTIVATING PROTEIN 1 TRANSCRIPTION FACTOR COMPLEX

A transcription-factor complex, which comprises a dimer of members of Fos and Jun families of nuclear phosphoproteins.

MORPHOGENESIS

The generation of an ordered form of a part, organ or organism through a collection of developmental processes.

IMAGINAL WING DISC

Single-cell layer epithelial structures of the Drosophila larva that gives rise to wings in the adult form.

NEUROGENESIS

The production of new nervous tissue.

EPISOMALLY REPLICATING PLASMID

A plasmid that can replicate extrachromosomally.

TRANSACTIVATION

The process by which genes are activated by means of a trans-activating domain that is contained in a transcription factor. This enables it to interact with proteins that are involved in binding RNA polymerase to DNA in a sequence-specific manner.

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Hazzalin, C., Mahadevan, L. MAPK-regulated transcription: a continuously variable gene switch?. Nat Rev Mol Cell Biol 3, 30–40 (2002). https://doi.org/10.1038/nrm715

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