Truncated PPM1D Prevents Apoptosis in the Murine Thymus and Promotes Ionizing Radiation-Induced Lymphoma

0539631 - ÚMG 2021 RIV CH eng J - Článek v odborném periodiku
Martiníková, Andra Stefania - Burocziová, Monika - Stoyanov, Miroslav - Macůrek, Libor
Truncated PPM1D Prevents Apoptosis in the Murine Thymus and Promotes Ionizing Radiation-Induced Lymphoma.
Cells. Roč. 9, č. 9 (2020), č. článku 2068. E-ISSN 2073-4409
Grant CEP: GA ČR GA20-11931S; GA MŠMT(CZ) LM2015040; GA MŠMT(CZ) ED1.1.00/02.0109; GA MŠMT(CZ) LM2015062; GA MŠMT LO1419
Institucionální podpora: RVO:68378050
Klíčová slova: cell-cycle checkpoint * tumor suppressor p53 * protein phosphatase * cancer
Obor OECD: Oncology
Impakt faktor: 6.600, rok: 2020
Způsob publikování: Open access
https://www.mdpi.com/2073-4409/9/9/2068

Genome integrity is protected by the cell-cycle checkpoints that prevent cell proliferation in the presence of DNA damage and allow time for DNA repair. The transient checkpoint arrest together with cellular senescence represent an intrinsic barrier to tumorigenesis. Tumor suppressor p53 is an integral part of the checkpoints and its inactivating mutations promote cancer growth. Protein phosphatase magnesium-dependent 1 (PPM1D) is a negative regulator of p53. Although its loss impairs recovery from the G2 checkpoint and promotes induction of senescence, amplification of thePPM1Dlocus or gain-of-function truncating mutations ofPPM1Doccur in various cancers. Here we used a transgenic mouse model carrying a truncating mutation in exon 6 ofPPM1D(Ppm1d(T)). As with human cell lines, we found that the truncated PPM1D was present at high levels in the mouse thymus. Truncated PPM1D did not affect differentiation of T-cells in the thymus but it impaired their response to ionizing radiation (IR). Thymocytes inPpm1d(T/+)mice did not arrest in the checkpoint and continued to proliferate despite the presence of DNA damage. In addition, we observed a decreased level of apoptosis in the thymi ofPpm1d(T/+)mice. Moreover, the frequency of the IR-induced T-cell lymphomas increased inPpm1d(T/+)Trp53(+/-)mice resulting in decreased survival. We conclude that truncated PPM1D partially suppresses the p53 pathway in the mouse thymus and potentiates tumor formation under the condition of a partial loss of p53 function.
Trvalý link: http://hdl.handle.net/11104/0317340