RPL23 Links Oncogenic RAS Signaling to p53-Mediated Tumor Suppression

Abstract

The ribosomal protein (RP)-MDM2 interaction is a p53 response pathway critical for preventing oncogenic c-MYC-induced tumorigenesis. To investigate whether the RP-MDM2-p53 pathway is a broad anti-oncogenic mechanism, we crossed mice bearing an MDM2C305F mutation, which disrupts RPL11 binding to MDM2, with mice expressing an oncogenic HrasG12V transgene. Interestingly, the MDM2C305F mutant mice, which are hypersensitive to c-MYC-induced tumorigenesis, are not hypersensitive to oncogenic HrasG12V-induced tumorigenesis. Unlike c-MYC, which induces expression of RPL11, RAS overexpression leads to an increase in RPL23 mRNA and protein while RPL11 expression remains unchanged. The induction of RPL23 involves both MEK and PI3K signaling pathways and requires mTOR function. Increased expression of RPL23, which maintains binding to MDM2C305F mutant, correlates with increased p53 expression in MDM2C305F cells. Furthermore, RAS overexpression can induce p53 in the absence of p19ARF, and the induction can be abolished by down-regulation of RPL23. Thus, while the RPL11-MDM2-p53 pathway coordinates with the p19ARF-MDM2-p53 pathway against oncogenic c-MYC-induced tumorigenesis, the RPL23-MDM2-p53 pathway coordinates with the p19ARF-MDM2-p53 pathway against oncogenic RAS-induced tumorigenesis.

Transcriptome and long noncoding RNA sequencing of three extracellular vesicle subtypes released from the human colon cancer LIM1863 cell line

“…Interestingly, most of the alternative spicing events occurred in ribosomal protein and TPT1 (TCTP) genes, whose normal transcripts are also highly expressed and enriched in the EVs (see above). While we do not see any splice variant forms of ribosomal or TCTP proteins in our datasets it is interesting to speculate that the corresponding transcripts we observe in EVs may be translated upon EV uptake in recipient cells; this, in turn, may contribute to onset of apoptosis and cancer, as described elsewhere353637.…”

Functional characterization of AMP-activated protein kinase signaling in tumorigenesis

“…Generally, activated p53 interacts with its tumor-inhibitory partners to initiate the growth-restricting pathways and repair DNA mismatches [187]. Specifically, as the downstream target of RP-MDM2 axis, p53 directly antagonizes RAS-involved tumorigenesis in rodent melanoma models [188]. Moreover, restoration of p53 could enhance the chemosensitivity of skin cancer cells by inducing the production of NEAT1 paraspeckles [189].…”

GRWD1 regulates ribosomal protein L23 levels via the ubiquitin-proteasome system

“…RPL5, RPL11 and RPL23 bind to MDM2 simultaneously, forming a heterotetramer within cells . Although knockdown of RPL5 or RPL11, but not RPL23, markedly inhibits Act D-driven p53 induction (Bursac et al, 2012;Nicolas et al, 2016), evidence suggests that RPL23 functions as a tumor suppressor (Meng et al, 2016;Zhang et al, 2010Zhang et al, , 2013. The present data suggest that GRWD1 acts together with the E3 ubiquitin ligase EDD [also known as human (h)HYD or UBR5] and proteolytically regulates RPL23, and that this regulatory mechanism may play a role in p53 downregulation by GRWD1.…”

“…In addition, RPL23 inhibits MDM2 ubiquitin ligase activity. Therefore, RPL23 may act as a tumor suppressor Jin et al, 2004;Meng et al, 2016;Zhang et al, 2010Zhang et al, , 2013. By contrast, our previous study identified GRWD1 as a novel negative regulator of p53 and a potential oncogene .…”