mTORC2 deploys the mRNA binding protein IGF2BP1 to regulate c-MYC expression and promote cell survival

Lambrianidou, Andromachi; Sereti, Evangelia; Soupsana, Katerina; Komini, Chrysoula; Dimas, Konstantinos; Trangas, Theoni

doi:10.1016/j.cellsig.2020.109912

Cited by 15 publications

(15 citation statements)

References 43 publications

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“… 190 IMP1 protects the coding region instability sequence of c-Myc mRNA against endonucleolytic cleavage. 191 Similarly, IMP1 can bind to KRAS mRNA and regulate its expression. Deletion of IMP1 significantly reduced KRAS expression.…”

Section: The Effect Of C-myc On Cancer Cells Metabolismmentioning

confidence: 99%

Target c-Myc to treat pancreatic cancer

Ala

2022

Cancer Biology & Therapy

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C-Myc overexpression is a common finding in pancreatic cancer and predicts the aggressive behavior of cancer cells. It binds to the promoter of different genes, thereby regulating their transcription. C-Myc is downstream of KRAS and interacts with several oncogenic and proliferative pathways in pancreatic cancer. C-Myc enhances aerobic glycolysis in cancer cells and regulates glutamate biosynthesis from glutamine. It provides enough energy for cancer cells’ metabolism and sufficient substrate for the synthesis of organic molecules. C-Myc overexpression is associated with chemoresistance, intra-tumor angiogenesis, epithelial-mesenchymal transition (EMT), and metastasis in pancreatic cancer. Despite its title, c-Myc is not “undruggable” and recent studies unveiled that it can be targeted, directly or indirectly. Small molecules that accelerate c-Myc ubiquitination and degradation have been effective in preclinical studies. Small molecules that hinder c-Myc-MAX heterodimerization or c-Myc/MAX/DNA complex formation can functionally inhibit c-Myc. In addition, c-Myc can be targeted through transcriptional, post-transcriptional, and translational modifications.

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Section: The Effect Of C-myc On Cancer Cells Metabolismmentioning

confidence: 99%

Target c-Myc to treat pancreatic cancer

Ala

2022

Cancer Biology & Therapy

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“…IMP1 is regulated in part via phosphorylation by either mTORC2 at S-181 or Src at Y-396 (Dai et al, 2013; Huttelmaier et al, 2005). Others reported recently diffuse cytoplasmic IMP1 in IMP1-S181A cells, and increased granule formation in IMP1-Y396F cells (Lambrianidou et al, 2021). In our hands, we confirm that IMP1-S181 contributes to diffuse cytoplasmic IMP1, however, we found additionally that cytoplasmic IMP1 decreased, and nuclear IMP1 expression increased, in IMP1-S181 mutant cells.…”

Section: Discussionmentioning

confidence: 92%

“…We next evaluated how p-IMP1 mutation affects its cellular localization, since prior studies suggest that IMP1 phosphorylation modulates IMP1 regulation of MYC (Lambrianidou et al, 2021). Imaging of GFP expression revealed primarily cytoplasmic staining in IMP1-WT-GFP , IMP1-Y396F-GFP , and IMP1-S181A/Y396F-GFP cells.…”

Section: Resultsmentioning

confidence: 99%

“…IMP1 contains a mTORC2-dependent phosphorylation site at serine 181 (S181) and a Src kinase- dependent site at tyrosine 398 (Y396) ( Figure 2A ), which can affect translation and/or localization of IMP1 targets (Dai et al, 2013; Huttelmaier et al, 2005; Lambrianidou et al, 2021). We therefore evaluated the relative contribution of IMP1 phosphorylation (p-IMP1) to its modulation of MAP1LC3B.…”

Section: Resultsmentioning

confidence: 99%

“…We evaluated IMP1 regulation of autophagy at the RNA and protein levels and via direct translational regulation using dual-luciferase reporter assays. We examined the relative contribution of phosphorylated IMP1 (p-IMP1), known to regulate transcript binding and translation in other contexts (Dai et al, 2013; Huttelmaier et al, 2005; Lambrianidou et al, 2021), to autophagy protein expression and IMP1 cytoplasmic localization. Finally, we evaluated IMP1 co-localization with autophagy transcripts at homeostasis and in response to arsenite-induced cell stress.…”

Section: Introductionmentioning

confidence: 99%

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IGF2BP1/IMP1 deletion enhances a facultative stem cell state via regulation ofMAP1LC3B

Parham

Williams

Chatterji³

et al. 2022

Preprint

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Homeostatic tissue maintenance requires coordinated regulation of metabolic processes including macroautophagy/autophagy. Autophagy dysregulation underlies numerous human diseases. Our prior work revealed that the RNA binding protein IGF2BP1/IMP1 binds transcripts encoding autophagy-related proteins. Furthermore, Imp1 deletion in gastrointestinal epithelial cells in mice was associated with enhanced autophagy flux and improved recovery from tissue injury. In the current study, we evaluated molecular mechanisms underlying IMP1 modulation of autophagy. We report increased expression of autophagy protein microtubule associated protein 1 light-chain 3B (MAP1LC3B) in cells with IMP1 deletion compared to control cells. MAP1LC3B expression was also increased in cells with mutated IMP1 phosphorylation sites. Luciferase reporter assays demonstrate increased translation of MAP1LC3B-3prime-UTR in cells with IMP1 deletion. Furthermore, we find that IMP1 co-localizes with MAP1LC3B transcripts at homeostasis, and co-localization is decreased in cells where IMP1 phosphorylation sites are mutated. IMP1 localization with MAP1LC3B transcripts is also decreased following cell stress. Taken together, our data support a model whereby IMP1 regulates MAP1LC3B translation which can serve as a mechanism to calibrate autophagy levels in the cell. This new mechanism may be particularly important in gastrointestinal epithelial cells, where autophagy is essential for tissue recovery following injury, or in diseases such as inflammatory bowel disease where defective autophagy is implicated.

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Post‐Translational Modifications of RNA‐Modifying Proteins in Cellular Dynamics and Disease Progression

Lin,

et al. 2024

Advanced Science

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RNA‐modifying proteins, classified as “writers,” “erasers,” and “readers,” dynamically modulate RNA by adding, removing, or interpreting chemical groups, thereby influencing RNA stability, functionality, and interactions. To date, over 170 distinct RNA chemical modifications and more than 100 RNA‐modifying enzymes have been identified, with ongoing research expanding these numbers. Although significant progress has been made in understanding RNA modification, the regulatory mechanisms that govern RNA‐modifying proteins themselves remain insufficiently explored. Post‐translational modifications (PTMs) such as phosphorylation, ubiquitination, and acetylation are crucial in modulating the function and behavior of these proteins. However, the full extent of PTM influence on RNA‐modifying proteins and their role in disease development remains to be fully elucidated. This review addresses these gaps by offering a comprehensive analysis of the roles PTMs play in regulating RNA‐modifying proteins. Mechanistic insights are provided into how these modifications alter biological processes, contribute to cellular function, and drive disease progression. In addition, the current research landscape is examined, highlighting the therapeutic potential of targeting PTMs on RNA‐modifying proteins for precision medicine. By advancing understanding of these regulatory networks, this review seeks to facilitate the development of more effective therapeutic strategies and inspire future research in the critical area of PTMs in RNA‐modifying proteins.

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mTORC2 deploys the mRNA binding protein IGF2BP1 to regulate c-MYC expression and promote cell survival

Cited by 15 publications

References 43 publications

Target c-Myc to treat pancreatic cancer

Target c-Myc to treat pancreatic cancer

IGF2BP1/IMP1 deletion enhances a facultative stem cell state via regulation ofMAP1LC3B

Post‐Translational Modifications of RNA‐Modifying Proteins in Cellular Dynamics and Disease Progression

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