scholarly journals Ribosomal protein S14 unties the MDM2–p53 loop upon ribosomal stress

Oncogene ◽  
2012 ◽  
Vol 32 (3) ◽  
pp. 388-396 ◽  
Author(s):  
X Zhou ◽  
Q Hao ◽  
J Liao ◽  
Q Zhang ◽  
H Lu
Keyword(s):  
Ribosomal Protein ◽  
Ribosomal Stress

scholarly journals Interplay between Ribosomal Protein S27a and MDM2 Protein in p53 Activation in Response to Ribosomal Stress

2011 ◽  
Vol 286 (26) ◽  
pp. 22730-22741 ◽  
Author(s):  
Xiao-Xin Sun ◽  
Tiffany DeVine ◽  
Kishore B. Challagundla ◽  
Mu-Shui Dai
Keyword(s):  
Ribosomal Protein ◽  
Mdm2 Protein ◽  
P53 Activation ◽  
Ribosomal Stress

scholarly journals Ribosomal Protein L11 Recruits miR-24/miRISC To Repress c-Myc Expression in Response to Ribosomal Stress

2011 ◽  
Vol 31 (19) ◽  
pp. 4007-4021 ◽  
Author(s):  
K. B. Challagundla ◽  
X.-X. Sun ◽  
X. Zhang ◽  
T. DeVine ◽  
Q. Zhang ◽  
...  
Keyword(s):  
Ribosomal Protein ◽  
Ribosomal Protein L11 ◽  
Ribosomal Stress

P53 is Activated without RPL11 Upregulation in Diamond-Blackfan Anemia,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3432-3432
Author(s):  
Hong-Yan Du ◽  
M. Tarek Elghetany ◽  
Blanche P Alter ◽  
Akiko Shimamura
Keyword(s):  
Bone Marrow ◽  
Ribosomal Protein ◽  
Ribosomal Proteins ◽  
Mrna Levels ◽  
Protein Levels ◽  
Diamond Blackfan Anemia ◽  
Human Cd34 ◽  
Cd34 Cells ◽  
P53 Activation ◽  
Ribosomal Stress

Abstract Abstract 3432 Diamond-Blackfan anemia (DBA) is an autosomal dominantly inherited bone marrow failure syndrome characterized by red cell aplasia, physical anomalies, and cancer predisposition. DBA is caused by mutations resulting in haploinsufficiency of genes encoding ribosomal proteins. p53 is activated in the erythroid lineage following reduction of ribosomal protein expression; however the mechanism whereby ribosomal stress results in p53 activation in DBA remains unclear. RPL11 has been proposed to play a central role in p53 activation following ribosomal stress. Reduced expression of individual small ribosomal subunit proteins in a tumor cell line resulted in increased translation of RPL11. Excess free RPL11 can bind and inactivate HDM2, an E3 ubiquitin ligase targeting p53 for degradation. The recent demonstration that cellular responses to ribosomal perturbations vary widely between different tissues raised the question of whether RPL11 upregulation contributes to p53 activation following ribosomal stress in hematopoietic progenitors. To address this question, we modeled DBA in human CD34+ cells. Since RPS19 is the most commonly mutated gene in DBA, we used lentiviral vectors expressing short hairpin RNAs to knock down RPS19 expression in primary human CD34+ cells. RPS19 protein levels were reduced to about 50% of control levels in a manner reflecting the haploinsufficient state in DBA. RPS19 depletion resulted in elevated p53 protein levels and increased mRNA levels of p21, a transcriptional target of p53. Total p53 mRNA levels and p53 mRNA translational activity remained unchanged consistent with a post-transcriptional mechanism for p53 activation. Although total RPL11 mRNA levels were not diminished following RPS19 depletion, RPL11 protein levels were significantly decreased consistent with post-transcriptional downregulation. Depletion of RPS19 in human CD34+ cells did not affect polysome loading of RPL11 mRNA. Reduction of additional ribosomal proteins also accompanied RPS19 knockdown consistent with coordinate regulation of multiple ribosomal protein levels. Corticosteroids, which improve anemia in the majority of DBA patients, did not prevent p53 activation, nor did this improve RPS19 or RPL11 protein levels. Expression of p53 was also assessed in bone marrow biopsy slides from 26 DBA patients with the following genotypes: RPS19 (18), RPS24 (2), RPS26 (2), RPS10 (1), RPS17 (1), RPS7 (1), and RPL11 (1). p53 was over-expressed in all but one patient (RPS26), and was clearly over-expressed in the DBA patient harboring the RPL11 mutation. In summary, we find that p53 activation in DBA does not require upregulation of RPL11 translation or elevated RPL11 protein levels. p53 activation persists in DBA caused by RPL11 deficiency. Corticosteroids do not improve ribosomal protein levels nor do they prevent p53 activation. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Regulation of the HDM2-p53 pathway by ribosomal protein L6 in response to ribosomal stress

2013 ◽  
Vol 42 (3) ◽  
pp. 1799-1811 ◽  
Author(s):  
Dongmei Bai ◽  
Jinfang Zhang ◽  
Weichun Xiao ◽  
Xiaofeng Zheng
Keyword(s):  
Ribosomal Protein ◽  
P53 Pathway ◽  
Ribosomal Stress

scholarly journals USP47 Promotes Tumorigenesis by Negative Regulation of p53 through Deubiquitinating Ribosomal Protein S2

Cancers ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 1137 ◽  
Author(s):  
Jinhong Cho ◽  
Jinyoung Park ◽  
Sang Chul Shin ◽  
Mihue Jang ◽  
Jae-Hong Kim ◽  
...  
Keyword(s):  
Ribosomal Protein ◽  
Xenograft Model ◽  
Deubiquitinating Enzymes ◽  
Potential Therapeutic Target ◽  
Mouse Xenograft Model ◽  
Specific Protease ◽  
Important Regulator ◽  
Ubiquitin Specific Protease ◽  
Cellular Stresses ◽  
Ribosomal Stress

p53 is activated in response to cellular stresses such as DNA damage, oxidative stress, and especially ribosomal stress. Although the regulations of p53 by E3 ligase and deubiquitinating enzymes (DUBs) have been described, the cellular roles of DUB associated with ribosomal stress have not been well studied. In this study, we report that Ubiquitin Specific Protease 47 (USP47) functions as an important regulator of p53. We show that ubiquitinated ribosomal protein S2 (RPS2) by Mouse double minute 2 homolog (MDM2) is deubiquitinated by USP47. USP47 inhibits the interaction between RPS2 and MDM2 thereby alleviating RPS2-mediated suppression of MDM2 under normal conditions. However, dissociation of USP47 leads to RPS2 binding to MDM2, which is required for the suppression of MDM2, consequently inducing up-regulation of the p53 level under ribosomal stress. Finally, we show that depletion of USP47 induces p53 and therefore inhibits cell proliferation, colony formation, and tumor progression in cancer cell lines and a mouse xenograft model. These findings suggest that USP47 could be a potential therapeutic target for cancer.

scholarly journals Proapoptotic Requirement of Ribosomal Protein L11 in Ribosomal Stress-Challenged Cortical Neurons

2016 ◽  
Vol 55 (1) ◽  
pp. 538-553 ◽  
Author(s):  
Lukasz P. Slomnicki ◽  
Justin Hallgren ◽  
Aruna Vashishta ◽  
Scott C. Smith ◽  
Steven R. Ellis ◽  
...  
Keyword(s):  
Ribosomal Protein ◽  
Cortical Neurons ◽  
Ribosomal Protein L11 ◽  
Ribosomal Stress

scholarly journals Transcriptome analysis reveals the differences between cellular response to ribosomal stress and translational stress

2017 ◽  
Author(s):  
Md Shamsuzzaman ◽  
Brian Gregory ◽  
Vincent Bruno ◽  
Lasse Lindahl
Keyword(s):  
Oxidative Stress ◽  
Gene Expression ◽  
Cell Wall ◽  
Cell Division ◽  
Cell Growth ◽  
Cell Membrane ◽  
Ribosomal Protein ◽  
Ribosome Biogenesis ◽  
Responsive Gene ◽  
Ribosomal Stress

AbstractRibosome biogenesis is an essential metabolic process of a growing cell. Cells need to continuously synthesize new ribosomes in order to make new proteins than can support building biomass and cell division. It is obvious that in the absence of ribosome biogenesis, cell growth will stop and cell division will stall. However, it is not clear whether cell growth stops due to reduced protein synthesis capacity (translational stress) or due to activation of signaling specific to ribosome biogenesis abnormalities (ribosomal stress). To understand the signaling pathways leading to cell cycle arrest under ribosomal and translational stress conditions, we performed time series RNA-seq experiments of cells at different time of ribosomal and translational stress. We found that expression of ribosomal protein genes follow different course over the time of these two stress types. In addition, ribosomal stress is sensed early in the cell, as early as 2hr. Up-regulation of genes responsive to oxidative stress and over representation of mRNAs for transcription factors responsive to stress was detected in cell at 2hr of ribosomal protein depletion. Even though, we detected phenotypic similarities in terms of cell separation and accumulation in G1 phase cells during inhibition of ribosome formation and ribosome function, different gene expression patterns underlie these phenotypes, indicating a difference in causalities of these phenotypes. Both ribosomal and translational stress show common increased expression of stress responsive gene expression, like Crz1 target gene expression, signature of oxidative stress response and finally membrane or cell wall instability. We speculate that cell membrane and cell wall acts as major stress sensor in the cell and adjust cellular metabolism accordingly. Any change in membrane lipid composition, or membrane protein oxidation, or decrease or increase in intracellular turgor pressure causes stress in cell membrane. Cell membrane or cell wall stress activates and/or inactivates specific signaling pathway which triggers stress responsive gene expression and adaptation of cellular behavior accordingly.

scholarly journals Ribosomal protein S27-like is a physiological regulator of p53 that suppresses genomic instability and tumorigenesis

eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
Xiufang Xiong ◽  
Yongchao Zhao ◽  
Fei Tang ◽  
Dongping Wei ◽  
Daffyd Thomas ◽  
...  
Keyword(s):  
Ribosomal Protein ◽  
Genomic Instability ◽  
Ribosomal Proteins ◽  
Selection Pressure ◽  
New Paradigm ◽  
Hematopoietic Stem ◽  
Mouse Knockout ◽  
Physiological Regulator ◽  
Ribosomal Stress ◽  
Dual Functions

Cell-based studies showed that several Mdm2-binding ribosomal proteins, upon overexpression, stabilize and activate p53. In contrast, here we show in a mouse knockout study that Mdm2-binding ribosomal protein S27-like (Rps27l), upon disruption, activates p53. Germline inactivation of Rps27l triggers ribosomal stress to stabilize Mdm2, which degrades Mdm4 to reduce Mdm2-Mdm4 E3 ligase towards p53, leading to p53-dependent apoptotic depletion of hematopoietic stem cells and postnatal death, which is rescued by Trp53 deletion. Paradoxically, while increased p53 is expected to inhibit tumorigenesis, Rps27l−/−;Trp53+/− mice develop lymphomas at higher incidence with p53 loss-of-heterozygosity and severe genome aneuploidy, suggesting that Rps27l disruption impose a selection pressure against p53. Thus, Rps27l has dual functions in p53 regulation: under Trp53+/+ background, Rps27l disruption triggers ribosomal stress to induce p53 and apoptosis, whereas under Trp53+/− background, Rps27l disruption triggers genomic instability and Trp53 deletion to promote tumorigenesis. Our study provides a new paradigm of p53 regulation.

scholarly journals Ribosomal stress-induced senescence as a novel pro-senescence strategy for p16 positive basal-like breast cancer

2018 ◽  
Author(s):  
Madeleine Moore ◽  
Luke Gammon ◽  
Sally Dreger ◽  
James Koh ◽  
James C Garbe ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Ribosomal Protein ◽  
Ribosomal Proteins ◽  
Disease Onset ◽  
Tissue Microarrays ◽  
Transcriptional Level ◽  
Protein Loss ◽  
Specific Subset ◽  
Basal Like Breast Cancer ◽  
Ribosomal Stress

ABSTRACTRe-engaging the senescent programme represents an attractive yet underexplored strategy for cancer therapy, particularly for those tumour subtypes where targeted agents are limited or unavailable. Here, we identify a specific subset of ribosomal proteins as novel pro-senescence therapeutic targets for a highly aggressive subtype of breast cancer, p16 positive basal-like breast cancer. Mechanistically, ribosomal stress-induced senescence generates a stable cell cycle arrest, is dependent on endogenous p16 triggering a resensitisation to the p16/RB tumour suppressor axis, followed by establishment of a senescence-associated secretory phenotype, and is independent of DNA damage. Conversely, ribosomal protein knockdown in a p16 negative breast cancer model results in caspase-mediated apoptosis. Importantly, individual ribosomal protein loss is well tolerated by a panel of normal human cells. We demonstrate a reciprocal feedback loop between loss of RPS3A and RPS7 at both the transcriptional and post-transcriptional level during ribosomal stress-induced senescence. Further, our ribosomal hits are co-ordinately dysregulated in breast cancer, with elevated expression associated with a poor prognosis. Clinical relevance is demonstrated in tissue microarrays, and a RPS3AHIGHRPS7HIGHsignature is associated with an earlier disease onset and synergises with p16 to further worsen patient outcome. We conclude that dysregulation of ribosomal proteins constitutes a cancer cell-specific mechanism of senescence evasion and that engaging ribosomal stress-induced senescence may be relevant for future pro-senescence therapies.

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