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Methods to Classify Cytoplasmic Foci as Mammalian Stress Granules
Published on: May 12, 2017
Ribosomal proteins as unrevealed caretakers for cellular stress and genomic instability
Tae-Hyung Kim1, Patrick Leslie, Yanping Zhang
1Department of Radiation Oncology, University of North Carolina, Chapel Hill, NC, USA.
Abstract:
Ribosomal proteins (RPs) have gained much attention for their extraribosomal functions particularly with respect to p53 regulation. To date, about fourteen RPs have shown to bind to MDM2 and regulate p53. Upon binding to MDM2, the RPs suppress MDM2 E3 ubiquitin ligase activity resulting in the stabilization and activation of p53. Of the RPs that bind to MDM2, RPL5 and RPL11 are the most studied and RPL11 appears to have the most significant role in p53 regulation. Considering that more than 17% of RP species have been shown to interact with MDM2, one of the questions remains unresolved is why so many RPs bind MDM2 and modulate p53. Genes encoding RPs are widely dispersed on different chromosomes in both mice and humans. As components of ribosome, RP expression is tightly regulated to meet the appropriate stoichiometric ratio between RPs and rRNAs. Once genomic instability (e.g. aneuploidy) occurs, transcriptional and translational changes due to change of DNA copy number can result in an imbalance in the expression of RPs including those that bind to MDM2. Such an imbalance in RP expression could lead to failure to assemble functional ribosomes resulting in ribosomal stress. We propose that RPs have evolved ability to regulate MDM2 in response to genomic instability as an additional layer of p53 regulation. Full understanding of the biological roles of RPs could potentially establish RPs as a novel class of therapeutic targets in human diseases such as cancer.
Insights
Ribosomal proteins (RPs) regulate the p53 pathway by inhibiting MDM2. This mechanism may have evolved to address genomic instability, offering potential therapeutic targets in cancer.
Area of Science:
- Molecular Biology
- Cell Biology
- Genetics
Background:
- Ribosomal proteins (RPs) exhibit extraribosomal functions, notably in regulating the p53 tumor suppressor.
- Over 14 RPs bind MDM2, inhibiting its ligase activity and stabilizing p53, with RPL11 being a key player.
- The extensive interaction of RPs with MDM2 suggests an underlying regulatory role beyond ribosome assembly.
Purpose of the Study:
- To investigate the reason behind the numerous ribosomal proteins (RPs) interacting with MDM2.
- To explore the link between RP expression imbalance, ribosomal stress, and p53 regulation.
- To propose RPs as a novel regulatory mechanism for p53 in response to genomic instability.
Main Methods:
- Literature review and analysis of existing data on RP-MDM2 interactions.
- Examination of the consequences of genomic instability on RP expression and ribosome biogenesis.
- Hypothesizing the evolutionary advantage of RP-mediated p53 regulation.
Main Results:
- Genomic instability can disrupt the stoichiometric balance of RP expression, leading to ribosomal stress.
- This ribosomal stress triggers RPs to bind MDM2, thereby activating the p53 pathway.
- RPs act as a critical link between genomic integrity and p53 activation.
Conclusions:
- RPs have evolved an additional layer of p53 regulation mediated by MDM2 in response to genomic instability.
- Understanding these extraribosomal functions of RPs could reveal novel therapeutic strategies for cancer.
- RPs represent a potential new class of therapeutic targets for human diseases, particularly cancer.
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