2. Academic Validation
  3. PPM1D activity promotes cellular transformation by preventing senescence and cell death

PPM1D activity promotes cellular transformation by preventing senescence and cell death

  • Oncogene. 2024 Sep 5. doi: 10.1038/s41388-024-03149-3.
Miroslav Stoyanov 1 2,  Andra S Martinikova 1,  Katerina Matejkova 3 4,  Klara Horackova 3,  Petra Zemankova 3,  Kamila Burdova 1,  Zuzana Zemanova 3,  Petra Kleiblova 3 5,  Zdenek Kleibl 3,  Libor Macurek 6
Affiliations

Affiliations

  • 1 Cancer Cell Biology, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic.
  • 2 Department of Cell Biology, Faculty of Science, Charles University, Prague, Czech Republic.
  • 3 Institute of Medical Biochemistry and Laboratory Diagnostics, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic.
  • 4 Department of Genetics and Microbiology, Faculty of Science, Charles University, Prague, Czech Republic.
  • 5 Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic.
  • 6 Cancer Cell Biology, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic. libor.macurek@img.cas.cz.
PMID: 39237765 DOI: 10.1038/s41388-024-03149-3
Abstract

Cell cycle checkpoints, oncogene-induced senescence and programmed cell death represent intrinsic barriers to tumorigenesis. Protein Phosphatase magnesium-dependent 1 (PPM1D) is a negative regulator of the tumour suppressor p53 and has been implicated in termination of the DNA damage response. Here, we addressed the consequences of increased PPM1D activity resulting from the gain-of-function truncating mutations in exon 6 of the PPM1D. We show that while control cells permanently exit the cell cycle and reside in senescence in the presence of DNA damage caused by ionising radiation or replication stress induced by the active Ras oncogene, RPE1-hTERT and BJ-hTERT cells carrying the truncated PPM1D continue proliferation in the presence of DNA damage, form micronuclei and accumulate genomic rearrangements revealed by karyotyping. Further, we show that increased PPM1D activity promotes cell growth in the soft agar and formation of tumours in xenograft models. Finally, expression profiling of the transformed clones revealed dysregulation of several oncogenic and tumour suppressor pathways. Our data support the oncogenic potential of PPM1D in the context of exposure to ionising radiation and oncogene-induced replication stress.

Figures
Products