The p38α stress kinase suppresses aneuploidy tolerance by inhibiting Hif-1α

Susana Simões-Sousa, Samantha Littler, Sarah Thompson, Paul Minshall, Helen Whalley, Bjorn Bakker, Klaudyna Belkot, Daniela Moralli, Daniel Bronder, Anthony Tighe, Diana Spierings, Nourdine Bah, Joshua Graham, Louisa Nelson, Catherine Green, Floris Foijer, Paul Townsend, Stephen Taylor

Research output: Contribution to journalArticlepeer-review


Deviating from the normal karyotype dramatically changes gene dosage, in turn decreasing the robustness of biological networks. Consequently, aneuploidy is poorly tolerated by normal somatic cells and acts as a barrier to transformation. Paradoxically however, karyotype heterogeneity drives tumour evolution and the emergence of therapeutic drug resistance. To better understand how cancer cells tolerate aneuploidy, we focused on the p38 stress response kinase. We show here that p38-deficient cells upregulate glycolysis and avoid post-mitotic apoptosis, leading to the emergence of aneuploid subclones. We also show that p38-deficiency upregulates the hypoxia-inducible transcription factor Hif-1α, and that inhibiting Hif-1α restores apoptosis in p38-deficent cells. Because hypoxia and aneuploidy are both barriers to tumour progression, the ability of Hif-1α to promote cell survival following chromosome missegregation raises the possibility that aneuploidy tolerance co-evolves with adaptation to hypoxia.
Original languageEnglish
Pages (from-to)749-760.e6
JournalCell Reports
Issue number3
Publication statusPublished - 16 Oct 2018


  • aneuploidy
  • chromosome instability
  • mitosis

Research Beacons, Institutes and Platforms

  • Manchester Cancer Research Centre


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