title: Regulation of the MDM2-P53 pathway and tumor growth by PICT1 via nucleolar RPL11.
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 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.
authors.affiliation: Global Centers of Excellence Program, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Sasaki
authors.forename: Kohichi
authors.initials: K
authors.lastname: Kawahara
authors.forename: Miki
authors.initials: M
authors.lastname: Nishio
authors.forename: Koshi
authors.initials: K
authors.lastname: Mimori
authors.forename: Ryunosuke
authors.initials: R
authors.lastname: Kogo
authors.forename: Koichi
authors.initials: K
authors.lastname: Hamada
authors.forename: Bunsho
authors.initials: B
authors.lastname: Itoh
authors.forename: Jia
authors.initials: J
authors.lastname: Wang
authors.forename: Yukako
authors.initials: Y
authors.lastname: Komatsu
authors.forename: Yong Ryoul
authors.initials: YR
authors.lastname: Yang
authors.forename: Hiroki
authors.initials: H
authors.lastname: Hikasa
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Horie
authors.forename: Takayuki
authors.initials: T
authors.lastname: Yamashita
authors.forename: Takehiko
authors.initials: T
authors.lastname: Kamijo
authors.forename: Yanping
authors.initials: Y
authors.lastname: Zhang
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhu
authors.forename: Carol
authors.initials: C
authors.lastname: Prives
authors.forename: Toru
authors.initials: T
authors.lastname: Nakano
authors.forename: Tak Wah
authors.initials: TW
authors.lastname: Mak
authors.forename: Takehiko
authors.initials: T
authors.lastname: Sasaki
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Maehama
authors.forename: Masaki
authors.initials: M
authors.lastname: Mori
authors.forename: Akira
authors.initials: A
authors.lastname: Suzuki
mesh_terms: D000818:Animals; D015152:Blotting, Northern; D002466:Cell Nucleolus / Q000378:metabolism; D049109:Cell Proliferation; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D015151:Immunoblotting; D020287:In Situ Nick-End Labeling; D007211:Indoles; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D009369:Neoplasms / Q000378:metabolism* / Q000503:physiopathology; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012269:Ribosomal Proteins / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D007211:Indoles; C500712:NOP53 protein, human; D012269:Ribosomal Proteins; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C027624:ribosomal protein L11; C007293:DAPI; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2