RIOK1 mediates p53 degradation and radioresistance in colorectal cancer through phosphorylation of G3BP2

Chen, Yaqi; Zhou, Sha; Wan, Kairui; Long, Yu; Zhao, Cheng; Deng, Haiteng; Ou, Qingjian; Qin, Jiayi; Hu, Junbo; Hou, Zhenlin

doi:10.1038/s41388-022-02352-4

Cited by 17 publications

(17 citation statements)

References 43 publications

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“…RIOK1 and RIOK2 have conserved roles in ribosomal RNA biogenesis and cell cycle progression [ 34 ]. Additional roles for RIO kinases have been suggested in diverse pathways, including protein arginine methylation [ 60 ], regulation of p53 activity and stability [ 61 , 62 ], and AKT [ 61 ] and p38 MAPK [ 63 , 64 ] signaling.…”

Section: Discussionmentioning

confidence: 99%

Pathways controlling neurotoxicity and proteostasis in mitochondrial complex I deficiency

Nithianandam,

Sarkar,

Feany

2024

Human Molecular Genetics

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Neuromuscular disorders caused by dysfunction of the mitochondrial respiratory chain are common, severe and untreatable. We recovered a number of mitochondrial genes, including electron transport chain components, in a large forward genetic screen for mutations causing age-related neurodegeneration in the context of proteostasis dysfunction. We created a model of complex I deficiency in the Drosophila retina to probe the role of protein degradation abnormalities in mitochondrial encephalomyopathies. Using our genetic model, we found that complex I deficiency regulates both the ubiquitin/proteasome and autophagy/lysosome arms of the proteostasis machinery. We further performed an in vivo kinome screen to uncover new and potentially druggable mechanisms contributing to complex I related neurodegeneration and proteostasis failure. Reduction of RIOK kinases and the innate immune signaling kinase pelle prevented neurodegeneration in complex I deficiency animals. Genetically targeting oxidative stress, but not RIOK1 or pelle knockdown, normalized proteostasis markers. Our findings outline distinct pathways controlling neurodegeneration and protein degradation in complex I deficiency and introduce an experimentally facile model in which to study these debilitating and currently treatment-refractory disorders.

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Section: Discussionmentioning

confidence: 99%

Pathways controlling neurotoxicity and proteostasis in mitochondrial complex I deficiency

Nithianandam,

Sarkar,

Feany

2024

Human Molecular Genetics

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“…Furthermore, p53 degradation was enhanced by MDM2-p53 interaction in oxaliplatin-resistant CRC cells [31]. Moreover, the RIOK1(RIO Kinase 1)-G3BP2(an RNA binding molecule)-MDM2 axis, facilitated the ubiquitination of p53, contributing to CRC radioresistance [32]. Moreover, MDM2-p53 was stabilized by prohibitin 2 to increase the eribulin resistance in gastric cancer [33].…”

Section: Discussionmentioning

confidence: 99%

Potential Biomarkers in Drug-Resistant Colorectal Cancer Cells

2022

Ann med clin Oncol

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Colorectal cancer contributed to the second cause of cancer-related death. Targeted therapy and chemotherapy seem not to reach the optimized response to the patients. More drug targets need to be identified. We screened 352 differentially expressed genes (DEGs) from three GEO datasets which contained MEK and CDK inhibitors as well as natural compounds that mediated drug resistance. STRING and Cytoscape databases plus GO annotation and KEGG pathway analysis narrowed 352 DEGs down to 4 candidate hub genes: VEGFA, IGF1R, FOS, and MDM2. The clinical significance of these 4 DEGs had been evaluated by overall survival rate using TCGA human patients' samples and protein staining using immunohistochemistry provided by the Human Protein Atlas (HPA) website. Our identified DEGs may serve as biomarkers for patients' prognosis or help reduce chemoresistance when combining those DEGs inhibitors with current clinical treatments.

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“…RIOK1 overexpression promotes cell migration and invasiveness via the epithelial-mesenchymal transition (EMT) pathway. Knocking down RioK1 annihilated EMT activity due to increased E-cadherin levels, decreased concentrations of Ncadherin, vimentin, and matrix metalloproteinase-2, caused by the downregulation of transcription factors STAT3 and TWIST1 [2,11,15,16]. Under the same conditions, oncogenic protein metadherin (MTDH), which promotes Akt-and NF-κB−mediated signalling and metastasis [17,18], is reduced in expression [15] (Fig.…”

Section: Riok1: a Multipurpose Kinase And Atpasementioning

confidence: 99%

“…A recent study by Chen et al [2] revealed that kinase/ATPase RioK1 promotes G3BP2 phosphorylation. This event instigates p53 ubiquitination and degradation, and provokes radiotherapy resistance.…”

Section: Introductionmentioning

confidence: 99%

The RioK1 network determines p53 activity at multiple levels

Damizia,

Moretta,

De Wulf

2023

Cell Death Discov.

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By responding to a host of adverse conditions, ranging from DNA damage to viral infection, transcription factor p53 supports genomic stability, cellular health, and survival. Not surprisingly, tumours across the cancer spectrum carry mutations in p53, misexpress the protein, or dysregulate its activity. Several signalling pathways, many of which comprise oncogenic proteins, converge upon p53 to control its stability and activity. We here present the conserved kinase/ATPase RioK1 as an upstream factor that determines p53 activity at the DNA, RNA, and protein levels. It achieves this task by integrating the regulatory events that act on p53 into a coherent response circuit. We will also discuss how RIOK1 overexpression represents an alternative mechanism for cancers to inactivate p53, and how targeting RioK1 could eradicate malignancies that are driven by a dysregulated RioK1-p53 network.

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RIOK1 mediates p53 degradation and radioresistance in colorectal cancer through phosphorylation of G3BP2

Cited by 17 publications

References 43 publications

Pathways controlling neurotoxicity and proteostasis in mitochondrial complex I deficiency

Pathways controlling neurotoxicity and proteostasis in mitochondrial complex I deficiency

Potential Biomarkers in Drug-Resistant Colorectal Cancer Cells

The RioK1 network determines p53 activity at multiple levels

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