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GRWD 1 negatively regulates p53 via the RPL 11– MDM 2 pathway and promotes tumorigenesis
Author(s) -
Kayama Kota,
Watanabe Shinya,
Takafuji Takuya,
Tsuji Takahiro,
Hironaka Kensuke,
Matsumoto Masaki,
Nakayama Keiichi I,
Enari Masato,
Kohno Takashi,
Shiraishi Kouya,
Kiyono Tohru,
Yoshida Kazumasa,
Sugimoto Nozomi,
Fujita Masatoshi
Publication year - 2017
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.201642444
Subject(s) - library science , carcinogenesis , biology , cancer , genetics , computer science
The ribosomal protein L11 ( RPL 11) binds and inhibits the MDM 2 ubiquitin ligase, thereby promoting p53 stability. Thus, RPL 11 acts as a tumor suppressor. Here, we show that GRWD 1 (glutamate‐rich WD 40 repeat containing 1) physically and functionally interacts with RPL 11. GRWD 1 is localized to nucleoli and is released into the nucleoplasm upon nucleolar stress. Silencing of GRWD 1 increases p53 induction by nucleolar stress, whereas overexpression of GRWD 1 reduces p53 induction. Furthermore, GRWD 1 overexpression competitively inhibits the RPL 11– MDM 2 interaction and alleviates RPL 11‐mediated suppression of MDM 2 ubiquitin ligase activity toward p53. These effects are mediated by the N‐terminal region of GRWD 1, including the acidic domain. Finally, we show that GRWD 1 overexpression in combination with HPV 16 E7 and activated KRAS confers anchorage‐independent growth and tumorigenic capacity on normal human fibroblasts. Consistent with this, GRWD 1 overexpression is associated with poor prognosis in cancer patients. Taken together, our results suggest that GRWD 1 is a novel negative regulator of p53 and a potential oncogene.