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.

• MeSH
• Cell Death genetics   MeSH
• Humans MeSH
• Mice MeSH
• Cell Transformation, Neoplastic * genetics   MeSH
• Tumor Suppressor Protein p53 genetics   metabolism   MeSH
• DNA Damage * genetics   MeSH
• Cell Proliferation genetics   MeSH
• Protein Phosphatase 2C * genetics   metabolism   MeSH
• Phosphoprotein Phosphatases genetics   metabolism   MeSH
• Cellular Senescence * genetics   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Tumor Suppressor Protein p53 MeSH
• PPM1D protein, human MeSH Browser
• Protein Phosphatase 2C * MeSH
• Phosphoprotein Phosphatases MeSH