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Mol Syst Biol. 2017 May 3;13(5):928. doi: 10.15252/msb.20177554.

An immediate-late gene expression module decodes ERK signal duration.

Author information

1
IRI Life Sciences & Institute for Theoretical Biology, Humboldt Universität Berlin, Berlin, Germany.
2
Institute of Pathology, Charité - Universitätsmedizin Berlin, Berlin, Germany.
3
Berlin Institute for Medical Systems Biology, Max Delbrück Center for Molecular Medicine, Berlin, Germany.
4
Berlin Institute of Health, Berlin, Germany.
5
IRI Life Sciences & Institute for Theoretical Biology, Humboldt Universität Berlin, Berlin, Germany nils.bluethgen@charite.de.

Abstract

The RAF-MEK-ERK signalling pathway controls fundamental, often opposing cellular processes such as proliferation and apoptosis. Signal duration has been identified to play a decisive role in these cell fate decisions. However, it remains unclear how the different early and late responding gene expression modules can discriminate short and long signals. We obtained both protein phosphorylation and gene expression time course data from HEK293 cells carrying an inducible construct of the proto-oncogene RAF By mathematical modelling, we identified a new gene expression module of immediate-late genes (ILGs) distinct in gene expression dynamics and function. We find that mRNA longevity enables these ILGs to respond late and thus translate ERK signal duration into response amplitude. Despite their late response, their GC-rich promoter structure suggested and metabolic labelling with 4SU confirmed that transcription of ILGs is induced immediately. A comparative analysis shows that the principle of duration decoding is conserved in PC12 cells and MCF7 cells, two paradigm cell systems for ERK signal duration. Altogether, our findings suggest that ILGs function as a gene expression module to decode ERK signal duration.

KEYWORDS:

ERK signalling; immediate–late genes; mRNA half‐life; signal decoding; signal duration

PMID:
28468958
PMCID:
PMC5448165
DOI:
10.15252/msb.20177554
[Indexed for MEDLINE]
Free PMC Article

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