An immediate–late gene expression module decodes ERK signal duration

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.

Widespread activation of antisense transcription of the host genome during herpes simplex virus 1 infection

“…3b , fourth panel; Additional file 1 : Figure S3a). IER2 is induced by the MAP kinase pathway [ 28 ], which is in turn activated by the infection itself [ 29 ]. Similarly to IER2, the pro-apoptotic gene ING1 [ 30 ] was induced by MAP kinases as well, and, like IER2, showed higher mRNA levels at all timepoints after infection compared to uninfected cells under PAA treatment.…”

Perturbation-response genes reveal signaling footprints in cancer gene expression

“…HEK293∆RAF1:ER cells were acquired and cultured as previously described 37 . Before treatments, cells were starved in serum-free medium overnight.…”

Communication codes in developmental signaling pathways

“…2C; Traverse et al, 1992), leading to the hypothesis that ERK dynamics could represent the activating ligand and receptor identity. Numerous subsequent studies in the same experimental system have revealed how pERK duration encoding and decoding arise both from the activity of the ligand-receptor complexes and downstream signal processing circuits (Kao et al, 2001;Marshall, 1995;Murphy et al, 2002Murphy et al, , 2004Santos et al, 2007;Sasagawa et al, 2005;Traverse et al, 1994;Uhlitz et al, 2017;Whitmarsh, 2007). Nevertheless, it has remained unclear to what extent transient and sustained ERK activity can explain the distinct cellular phenotypes, especially at the single cell level.…”