TY - JOUR
T1 - Regulation of the MDM2-P53 pathway and tumor growth by PICT1 via nucleolar RPL11
AU - Sasaki, Masato
AU - Kawahara, Kohichi
AU - Nishio, Miki
AU - Mimori, Koshi
AU - Kogo, Ryunosuke
AU - Hamada, Koichi
AU - Itoh, Bunsho
AU - Wang, Jia
AU - Komatsu, Yukako
AU - Yang, Yong Ryoul
AU - Hikasa, Hiroki
AU - Horie, Yasuo
AU - Yamashita, Takayuki
AU - Kamijo, Takehiko
AU - Zhang, Yanping
AU - Zhu, Yan
AU - Prives, Carol
AU - Nakano, Toru
AU - Mak, Tak Wah
AU - Sasaki, Takehiko
AU - Maehama, Tomohiko
AU - Mori, Masaki
AU - Suzuki, Akira
N1 - Funding Information:
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.
PY - 2011/8
Y1 - 2011/8
N2 - 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 G 1 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.
AB - 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 G 1 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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U2 - 10.1038/nm.2392
DO - 10.1038/nm.2392
M3 - Article
C2 - 21804542
AN - SCOPUS:79961145353
VL - 17
SP - 944
EP - 951
JO - Nature Medicine
JF - Nature Medicine
SN - 1078-8956
IS - 8
ER -
