RRC ID 57055
Author Kayama K, Watanabe S, Takafuji T, Tsuji T, Hironaka K, Matsumoto M, Nakayama KI, Enari M, Kohno T, Shiraishi K, Kiyono T, Yoshida K, Sugimoto N, Fujita M.
Title GRWD1 negatively regulates p53 via the RPL11-MDM2 pathway and promotes tumorigenesis.
Journal EMBO Rep
Abstract 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.
Volume 18(1)
Pages 123-137
Published 2017-1
DOI 10.15252/embr.201642444
PII embr.201642444
PMID 27856536
PMC PMC5210153
MeSH Animals Carrier Proteins / chemistry Carrier Proteins / metabolism* Cell Line, Tumor Cell Transformation, Neoplastic / genetics* Cell Transformation, Neoplastic / metabolism* Cell Transformation, Viral Disease Models, Animal Female Gene Expression Gene Expression Regulation, Neoplastic* Gene Silencing Genes, ras Heterografts Humans Mice Neoplasms / genetics Neoplasms / metabolism Neoplasms / mortality Neoplasms / pathology Prognosis Protein Binding Protein Interaction Domains and Motifs Protein Stability Proto-Oncogene Proteins c-mdm2 / metabolism* Ribosomal Proteins / metabolism* Signal Transduction* Stress, Physiological Tumor Suppressor Protein p53 / genetics* Tumor Suppressor Protein p53 / metabolism
IF 8.383
Times Cited 18
Resource
DNA material pFLAG-CMV-5a-RPL5 (RDB17329) pFLAG-CMV-5a-RPL11 (RDB17330)