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.
The ribosomal protein L11 (RPL11) functions as a tumor suppressor by inhibiting the MDM2 ubiquitin ligase that promotes degradation of p53. This study shows that GRWD1 (glutamate‐rich WD40 repeat containing 1) binds to RPL11, thereby counteracting RPL11‐mediated suppression of MDM2, and down‐regulating p53 levels.
GRWD1 binds to RPL11 and counteracts RPL11‐mediated suppression of MDM2 ubiquitin ligase, thereby down‐regulating p53.
GRWD1 in combination with HPV16 E7 and activated KRAS confers tumorigenicity on normal human fibroblasts and GRWD1 overexpression is associated with poor prognosis in cancer patients.
GRWD1 is a novel negative regulator of p53 and a potential oncogene.
- Received March 27, 2016.
- Revision received October 19, 2016.
- Accepted October 21, 2016.
- © 2016 The Authors