TY - JOUR
T1 - GRWD1 negatively regulates p53 via the RPL11–MDM2 pathway and promotes tumorigenesis
AU - Kayama, Kota
AU - Watanabe, Shinya
AU - Takafuji, Takuya
AU - Tsuji, Takahiro
AU - Hironaka, Kensuke
AU - Matsumoto, Masaki
AU - Nakayama, Keiichi I.
AU - Enari, Masato
AU - Kohno, Takashi
AU - Shiraishi, Kouya
AU - Kiyono, Tohru
AU - Yoshida, Kazumasa
AU - Sugimoto, Nozomi
AU - Fujita, Masatoshi
N1 - Funding Information:
We thank Dr. Bert Vogelstain for providing HCT116 cells (wild type and p53−/−) and M. Kosugi for technical and secretarial assistance. We are also grateful for technical support from the Research Support Center, Graduate School of Medical Sciences, Kyushu University. This work was supported in part by grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan to MF (21370084 and 25291027) and NS (25870509 and 15K18412) and by a grant to NS from the Uehara Memorial Foundation.
Publisher Copyright:
© 2016 The Authors
PY - 2017/1/1
Y1 - 2017/1/1
N2 - The ribosomal protein L11 (RPL11) binds and inhibits the MDM2 ubiquitin ligase, thereby promoting p53 stability. Thus, RPL11 acts as a tumor suppressor. Here, we show that GRWD1 (glutamate-rich WD40 repeat containing 1) physically and functionally interacts with RPL11. GRWD1 is localized to nucleoli and is released into the nucleoplasm upon nucleolar stress. Silencing of GRWD1 increases p53 induction by nucleolar stress, whereas overexpression of GRWD1 reduces p53 induction. Furthermore, GRWD1 overexpression competitively inhibits the RPL11–MDM2 interaction and alleviates RPL11-mediated suppression of MDM2 ubiquitin ligase activity toward p53. These effects are mediated by the N-terminal region of GRWD1, including the acidic domain. Finally, we show that GRWD1 overexpression in combination with HPV16 E7 and activated KRAS confers anchorage-independent growth and tumorigenic capacity on normal human fibroblasts. Consistent with this, GRWD1 overexpression is associated with poor prognosis in cancer patients. Taken together, our results suggest that GRWD1 is a novel negative regulator of p53 and a potential oncogene.
AB - The ribosomal protein L11 (RPL11) binds and inhibits the MDM2 ubiquitin ligase, thereby promoting p53 stability. Thus, RPL11 acts as a tumor suppressor. Here, we show that GRWD1 (glutamate-rich WD40 repeat containing 1) physically and functionally interacts with RPL11. GRWD1 is localized to nucleoli and is released into the nucleoplasm upon nucleolar stress. Silencing of GRWD1 increases p53 induction by nucleolar stress, whereas overexpression of GRWD1 reduces p53 induction. Furthermore, GRWD1 overexpression competitively inhibits the RPL11–MDM2 interaction and alleviates RPL11-mediated suppression of MDM2 ubiquitin ligase activity toward p53. These effects are mediated by the N-terminal region of GRWD1, including the acidic domain. Finally, we show that GRWD1 overexpression in combination with HPV16 E7 and activated KRAS confers anchorage-independent growth and tumorigenic capacity on normal human fibroblasts. Consistent with this, GRWD1 overexpression is associated with poor prognosis in cancer patients. Taken together, our results suggest that GRWD1 is a novel negative regulator of p53 and a potential oncogene.
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U2 - 10.15252/embr.201642444
DO - 10.15252/embr.201642444
M3 - Article
C2 - 27856536
AN - SCOPUS:85002973119
SN - 1469-221X
VL - 18
SP - 123
EP - 137
JO - EMBO Reports
JF - EMBO Reports
IS - 1
ER -
