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Ablation of a peptidyl prolyl isomerase Pin1 from p53-null mice accelerated thymic hyperplasia by increasing the level of the intracellular form of Notch1

Oncogene volume 26, pages 3835–3845 (2007)Cite this article

Abstract

Tumor suppressor p53 is essential for checkpoint control in response to a variety of genotoxic stresses. DNA damage leads to phosphorylation on the Ser/Thr-Pro motifs of p53, which facilitates interaction with Pin1, a pSer/pThr-Pro-specific peptidyl prolyl isomerase. Pin1 is required for the timely activation of p53, resulting in apoptosis or cell cycle arrest. To investigate the physiological relationship between Pin1 and p53, we created Pin1−/−p53−/− mice. These p53-deficient mice spontaneously developed lymphomas, mainly of thymic origin, as well as generalized lymphoma infiltration into other organs, including the liver, kidneys and lungs. Ablation of Pin1, in addition to p53, accelerated the thymic hyperplasia, but the thymocytes in these Pin1−/−p53−/− mice did not infiltrate other organs. The thymocytes in 12-week-old Pin1−/−p53−/− mice were CD4−CD8− (double negative) and had significantly higher levels of the intracellular form of Notch1 (NIC) than the thymocytes of p53−/− or wild-type mice. Presenilin-1, a cleavage enzyme for NIC generation from full-length Notch1 was increased in the thymocytes of Pin1−/−p53−/− mice. Pin1 depletion also inhibited the degradation of NIC by proteasomes. These results suggest that both Pin1 and p53 control the normal proliferation and differentiation of thymocytes by regulating the NIC level.

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Acknowledgements

We thank T Tachikawa, RW Shin and K Takeuchi for supporting the analysis of the histopathology of the mice. We thank A Kondoh and M Suzuki for taking care of the mice. K Fukuchi, T Hasegawa, K Ikeda, D Sato, Y Sano, K Saito, NH Choi-Miura and S Arata for their technical help, and L Ostroff for editorial assistance. This work was supported in part by a Grant-in-Aid for Scientific Research on Priority Areas (TU), Grant-in-Aid for Scientific Research (TU), and a Special Research Grant-in-Aid for Development of Characteristic Education (KT) from the Ministry of Education, Culture, Sports, Science and Technology of Japan, a Showa University Grant-in-Aid for Innovative Collaborative Research Projects (KT) and the Center for Interdisciplinary Research Tohoku University for Specially Promoted Research (TU).

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Authors and Affiliations

  1. Center for Interdisciplinary Research, Tohoku University, Sendai, Miyagi, Japan

    K Takahashi, H Akiyama, C Uchida & T Uchida

  2. Molecular Enzymology, Agricultural Science, Tohoku University, Sendai, Miyagi, Japan

    H Akiyama & T Uchida

  3. Institute of Development, Aging and Cancer, Tohoku University, Sendai, Miyagi, Japan

    M Fukumoto

  4. School of Pharmaceutical Sciences, Showa University, Tokyo, Japan

    K Takahashi, K Shimazaki, H Akiyama-Okunuki & M Tomita

  5. University Health Center, Ibaraki University, Mito, Ibaraki, Japan

    C Uchida

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Takahashi, K., Akiyama, H., Shimazaki, K. et al. Ablation of a peptidyl prolyl isomerase Pin1 from p53-null mice accelerated thymic hyperplasia by increasing the level of the intracellular form of Notch1. Oncogene 26, 3835–3845 (2007). https://doi.org/10.1038/sj.onc.1210153

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