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Regulation of the MDM2-P53 pathway and tumor growth by PICT1 via nucleolar RPL11

Nature Medicine volume 17, pages 944–951 (2011)Cite this article

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Abstract

PICT1 (also known as GLTSCR2) is considered a tumor suppressor because it stabilizes phosphatase and tensin homolog (PTEN), but individuals with oligodendrogliomas lacking chromosome 19q13, where PICT1 is located, have better prognoses than other oligodendroglioma patients. To clarify the function of PICT1, we generated Pict1-deficient mice and embryonic stem (ES) cells. Pict1 is a nucleolar protein essential for embryogenesis and ES cell survival. Even without DNA damage, Pict1 loss led to p53-dependent arrest of cell cycle phase G1 and apoptosis. Pict1-deficient cells accumulated p53, owing to impaired Mdm2 function. Pict1 binds Rpl11, and Rpl11 is released from nucleoli in the absence of Pict1. In Pict1-deficient cells, increased binding of Rpl11 to Mdm2 blocks Mdm2-mediated ubiquitination of p53. In human cancer, individuals whose tumors express less PICT1 have better prognoses. When PICT1 is depleted in tumor cells with intact P53 signaling, the cells grow more slowly and accumulate P53. Thus, PICT1 is a potent regulator of the MDM2-P53 pathway and promotes tumor progression by retaining RPL11 in the nucleolus.

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Figure 1: Pict1 loss impairs survival of mouse embryos and ES cells.
Figure 2: Effects of Pict1 deficiency are p53 dependent.
Figure 3: Pict1 deficiency inhibits Mdm2 function.
Figure 4: Pict1 regulates Mdm2 by binding to nucleolar Rpl11.
Figure 5: Reduced cancer growth and better survival with low PICT1.
Figure 6: PICT1 binding to nucleolar RPL11 regulates MDM2-P53 activity.

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Acknowledgements

We are grateful to T. Noda, S. Kuroda, H. Kishimoto, M. Natsui, H. Takahashi, H. Tashiro, N. Yasui, M. Suzuki, S. Suzuki, T. Shono and T. Sasaki for expert technical support and helpful discussions. We also thank H. Miyoshi (RIKEN BioResource Center, Tsukuba, Japan) for providing lentivirus vector plasmid DNA. This work was supported by grants from the Ministry of Education, Culture, Sports and Technology of Japan (MEXT), Takeda Medical Foundation, Naito Foundation, Ono Medical Research Foundation, Yasuda Medical Foundation, and Astellas Foundation for Research on Metabolic Disorders. K.M. and M.M. are supported by the Core Research for Evolutionary Science and Technology program of the Japanese Science and Technology Agency. T.Y., T.S., M.M. and A.S. are supported by the Global Centers of Excellence Program of MEXT.

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  1. Masato Sasaki and Kohichi Kawahara: These authors contributed equally to this work.

Authors and Affiliations

  1. Global Centers of Excellence Program, Akita University Graduate School of Medicine, Akita, Japan

    Masato Sasaki, Takehiko Sasaki & Akira Suzuki

  2. Division of Cancer Genetics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan

    Kohichi Kawahara, Miki Nishio, Koichi Hamada, Bunsho Itoh, Jia Wang, Yukako Komatsu, Yong Ryoul Yang, Hiroki Hikasa & Akira Suzuki

  3. Division of Molecular and Surgical Oncology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan

    Koshi Mimori, Ryunosuke Kogo & Masaki Mori

  4. Department of Gastroenterology, Akita University Graduate School of Medicine, Akita, Japan

    Yasuo Horie

  5. Laboratory of Molecular Genetics, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Japan

    Takayuki Yamashita

  6. Division of Biochemistry and Molecular Carcinogenesis, Chiba Cancer Center Research Institute, Chiba, Japan

    Takehiko Kamijo

  7. Department of Radiation Oncology and Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina, USA

    Yanping Zhang

  8. Department of Biological Sciences, Columbia University, New York, New York, USA

    Yan Zhu & Carol Prives

  9. Department of Pathology, Osaka University, Suita, Japan

    Toru Nakano

  10. The Campbell Family Institute for Cancer Research, University Health Network, Toronto, Ontario, Canada

    Tak Wah Mak

  11. Department of Medical Biology, Akita University Graduate School of Medicine, Akita, Japan

    Takehiko Sasaki

  12. Department of Biochemistry and Cell Biology, Japan National Institute of Infectious Diseases, Tokyo, Japan

    Tomohiko Maehama

  13. Department of Gastroenterological Surgery, Medical School and Graduate School of Frontier Biosciences, Osaka University, Suita, Japan

    Masaki Mori

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  1. Masato Sasaki
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Contributions

M.S. carried out the initial generation and analyses of Pict1flox mice and Pict1 ES cells. K.K. carried out subsequent major biochemical and biological experiments, and M.N. carried out mouse work. K.M., R.K. and M.M. carried out the human cancer tissue analyses. K.H. generated Pict1−/− mice. B.I. assisted with confocal microscopy. J.W., Y.K. and Y.R.Y. assisted with the introduction of shRNA into human cancer cell lines. H.H. assisted with the protein binding assays. Y.H. carried out mouse analyses. T.Y., T.K., Y. Zhang, Y. Zhu, C.P. and T.W.M. provided key materials. T.M., K.M. and A.S. conceived of the project, and M.S., K.K., K.M, T.M., M.M. and A.S. designed the experiments. M.S., K.K., M.N., K.M., R.K., T.Y., T.K., Y. Zhang, C.P., T.N., T.W.M., T.S., T.M., M.M. and A.S. discussed the hypothesis and interpreted the data. A.S. coordinated and directed the project and wrote the manuscript.

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Correspondence to Masaki Mori or Akira Suzuki.

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Sasaki, M., Kawahara, K., Nishio, M. et al. Regulation of the MDM2-P53 pathway and tumor growth by PICT1 via nucleolar RPL11. Nat Med 17, 944–951 (2011). https://doi.org/10.1038/nm.2392

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