An immediate–late gene expression module decodes ERK signal duration. Issue 5 (3rd May 2017)

• Record Type: Journal Article
• Authors: Uhlitz, Florian; Sieber, Anja; Wyler, Emanuel; Fritsche‐Guenther, Raphaela; Meisig, Johannes; Landthaler, Markus; Klinger, Bertram; Blüthgen, Nils
• Is Part Of: Molecular systems biology. Volume 13:Issue 5(2017:May)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2017-05-03
• Subjects: ERK signalling -- immediate–late genes -- mRNA half‐life -- signal decoding -- signal duration; Molecular biology -- Periodicals; Systems biology -- Periodicals; 572.8
• DOI: 10.15252/msb.20177554
• Languages: English
• ISSNs: 1744-4292

Abstract

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. Synopsis: A synthetic model system for ERK signalling identifies a class of immediate–late genes (ILGs) that respond immediately to ERK activity but with slow kinetics due to their long mRNA half‐lives. These ILGs can decode ERK signal duration into mRNA response amplitude. ILGs are primary response genes with long mRNA half‐lives. ILGs translate ERK signal duration into mRNA response amplitude in contrast to IEGs that only relay signal duration. The principle of duration decoding by ILGs is conserved in PC12 cells and MCF7 cells, two paradigm cell systems for ERK signal duration. Abstract : A synthetic model system for ERK signalling identifies a class of immediate–late genes (ILGs) that respond immediately to ERK activity but with slow kinetics due to their long mRNA half‐lives. These ILGs can decode ERK signal duration into mRNA response amplitude.