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Nucleic Acids Res. 2015 Nov 16;43(20):9663-79. doi: 10.1093/nar/gkv1015. Epub 2015 Oct 12.

Perturbations of PIP3 signalling trigger a global remodelling of mRNA landscape and reveal a transcriptional feedback loop.

Author information

1
Babraham Institute, Babraham Research Campus, Cambridge, CB22 3AT, UK.
2
London Research Institute, London, WC2A 3LY, UK.
3
Babraham Institute, Babraham Research Campus, Cambridge, CB22 3AT, UK EMBL-European Bioinformatics Institute, Hinxton, CB10 1SD, UK lenov@babraham.ac.uk.

Abstract

PIP3 is synthesized by the Class I PI3Ks and regulates complex cell responses, such as growth and migration. Signals that drive long-term reshaping of cell phenotypes are difficult to resolve because of complex feedback networks that operate over extended times. PIP3-dependent modulation of mRNA accumulation is clearly important in this process but is poorly understood. We have quantified the genome-wide mRNA-landscape of non-transformed, breast epithelium-derived MCF10a cells and its response to acute regulation by EGF, in the presence or absence of a PI3Kα inhibitor, compare it to chronic activation of PI3K signalling by cancer-relevant mutations (isogenic cells expressing an oncomutant PI3Kα allele or lacking the PIP3-phosphatase/tumour-suppressor, PTEN). Our results show that whilst many mRNAs are changed by long-term genetic perturbation of PIP3 signalling ('butterfly effect'), a much smaller number do so in a coherent fashion with the different PIP3 perturbations. This suggests a subset of more directly regulated mRNAs. We show that mRNAs respond differently to given aspects of PIP3 regulation. Some PIP3-sensitive mRNAs encode PI3K pathway components, thus suggesting a transcriptional feedback loop. We identify the transcription factor binding motifs SRF and PRDM1 as important regulators of PIP3-sensitive mRNAs involved in cell movement.

PMID:
26464442
PMCID:
PMC4787766
DOI:
10.1093/nar/gkv1015
[Indexed for MEDLINE]
Free PMC Article

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