Abstract PR9: PICT1/GLTSCR2 is a critical nucleolar binding partner of RPL11 that regulates the MDM2-p53 pathway and tumor growth
Authors: Kawahara Kohichi , Sasaki Masato , Nishio Miki , Mimori Koshi , Kogo Ryunosuke , Zhang Yanping , Maehama Tomohiko , Mori Masaki , Suzuki Akira 
Published: June 2012

Abstract
The tumor-suppressive MDM2-p53 intracellular signaling pathway is activated by cellular stress. Such stress includes DNA damage, which triggers the ATM-Chk2 and ATR-Chk1 cascades; infection or oncogene activation, which induce the p19ARF pathway; and nucleolar stress, which initiates a cascade mediated by ribosomal proteins (RPs), particularly RPL5, RPL11, RPL23, and RPS7. These RPs are usually located in the nucleolus but are rapidly released into the nucleoplasm upon nucleolar stress, activating the MDM2-p53 pathway. However, it is unknown whether there are direct connections between p53-activating RP genes and cancer development in vivo, and which mechanism these RPs employ to translocate from the nucleolus to the nucleoplasm in response to stress.
PICT1/GLTSCR2 was originally identified as a candidate tumor suppressor gene located at human chromosome 19q13.32, the site of deletions in human gliomas. Subsequent in vitro studies have demonstrated that PICT1 regulates the stability of PTEN, and that low PICT1 expression caused growth advantage. Based on these findings, PICT1 has been deemed a tumor suppressor. Other evidence, however, suggests that PICT1 may not always dampen cancer progression. In oligodendroglial tumors, loss of heterozygosity (LOH) at chromosome 19q13 is associated with longer disease-free survival after chemotherapy. These contradictory observations indicate that one or more genes mapped to chromosome 19q may contribute to brain cancer development. We speculated that PICT1 might be an important chromosome 19q–mapped gene that regulates tumor progression.
To clarify PICT1 function, we generated PICT1-deficient mice and ES cells and carried out extensive biochemical and molecular analyses. Our results show that PICT1 is a nucleolar protein essential for murine embryogenesis and ES cell survival. Even without DNA damage, PICT1 loss results in p53-dependent G1 arrest and apoptosis in vitro and in vivo. Strikingly, PICT1-deficient cells accumulate p53 due to impaired MDM2 function. We further show that PICT1 binds to RPL11, and that 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, leading to p53 accumulation and repression of cell proliferation. In cases of human colon and esophageal cancer, patients with low PICT1 expression have better prognoses. Similarly, when shRNA is used to deplete PICT1 in various tumor cell lines with intact p53 signaling, the cells grow more slowly and accumulate p53. These data suggest that PICT1 is a novel key regulator of the MDM2-p53 pathway and promotes tumor progression by retaining RPL11 in the nucleolus. Thus, PICT1 is an important cancer-related gene that, at the very least, does not behave like a typical tumor suppressor and may instead have oncogenic effects. Studies on identification of factors which influence PICT1 expression or stability, or interfering with PICT1-RPL11 binding may lead to new cancer therapeutics, especially for individuals with intact-p53 signaling.
This abstract is also presented as Poster B30.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr PR9.