Regulation of the MDM2-P53 pathway and tumor growth by PICT1 via nucleolar RPL11.
Regulation of the MDM2-P53 pathway and tumor growth by PICT1 via nucleolar RPL11.
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DOI：
10.1038/nm.2392
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发表时间：
2011-07-31
期刊：
影响因子：
82.9
通讯作者：
Suzuki A
中科院分区：
文献类型：
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作者：
Sasaki M;Kawahara K;Nishio M;Mimori K;Kogo R;Hamada K;Itoh B;Wang J;Komatsu Y;Yang YR;Hikasa H;Horie Y;Yamashita T;Kamijo T;Zhang Y;Zhu Y;Prives C;Nakano T;Mak TW;Sasaki T;Maehama T;Mori M;Suzuki A
PICT1(也称为GLTSCR2)被认为是一种肿瘤抑制因子，因为它稳定了磷酸酶和张力蛋白同源物(PTEN)，但PICT1所在的缺失19q13染色体的少突胶质瘤患者比其他少突胶质瘤患者预后更好。为了阐明PICT1的功能，我们产生了Pict1缺陷小鼠和胚胎干细胞。Pict1是胚胎发生和ES细胞存活所必需的核仁蛋白。即使在没有DNA损伤的情况下，Pict1的缺失也会导致P53依赖的细胞周期G1期停滞和细胞凋亡。由于MDM2功能受损，Pict1缺陷细胞积聚了P53。Pict1与Rpl11结合，在没有Pict1的情况下，Rpl11从核仁中释放出来。在Pict1缺陷细胞中，Rpl11与MDM2结合的增加阻止了MDM2介导的p53泛素化。在人类癌症中，肿瘤表达PICT1较少的个体预后较好。当PICT1在P53信号完整的肿瘤细胞中被耗尽时，细胞生长速度变慢，并积累P53。因此，PICT1是MDM2-P53通路的有效调节者，并通过将RPL11保留在核仁中而促进肿瘤进展
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