Characterization of developmental defects in the forebrain resulting from hyperactivated mTOR signaling by integrative analysis of transcriptomic and proteomic data

Shin, Jiheon; Kim, Minhyung; Jung, Hee Jung; Lim, Hye Jin; Suh‐Kim, Haeyoung; Ahn, Sanghyun; Jung, Jae‐Hoon; Kim, Youn Ah; Jun, Yukyung; Lee, Sanghyuk; Hwang, Daehee; Kim, Jaesang

doi:10.1038/s41598-017-02842-6

Cited by 12 publications

(9 citation statements)

References 45 publications

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“…5a, b). Supporting these findings, we interrogated by GSEA analysis genes known to be targeted by hyperactivated mTOR signaling in TSC1 KO 34 , which revealed an enrichment in DS ( p < 0.001, FDR q < 0.001; Fig. 5c).…”

Section: Resultssupporting

confidence: 52%

“…b Phosphorylation levels quantified by densitometry as a ratio of phospho-protein/total protein level ( n ≥ 3). c GSEA of transcriptome changes comparing DS fibroblasts to 2 N fibroblasts, using a list of genes described to be upregulated upon hyperactivated mTOR signaling due to Tsc1 depletion (Shin et al 34 ). As described for Figs.…”

Section: Resultsmentioning

confidence: 99%

“…Gene sets were considered to be significantly enriched if the adjusted (Benjamini–Hochberg) p -value, i.e., FDR ( q -value) was <0.01 in pairwise comparisons using 100,000 random rotation. ROAST were used on the mTOR targets list, which was obtained from those genes described to be upregulated upon constitutive hyperactivation of mTOR caused by TSC1 KO; 34 the list of transcriptional factors described to be essential for supporting mitophagy activation and the list of transcriptional factors regulating mitochondrial biogenesis are described in Supplementary Table 1.…”

Section: Methodsmentioning

confidence: 99%

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mTOR hyperactivation in Down Syndrome underlies deficits in autophagy induction, autophagosome formation, and mitophagy

et al. 2019

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Down syndrome (DS), a complex genetic disorder caused by chromosome 21 trisomy, is associated with mitochondrial dysfunction leading to the accumulation of damaged mitochondria. Here we report that mitophagy, a form of selective autophagy activated to clear damaged mitochondria is deficient in primary human fibroblasts derived from individuals with DS leading to accumulation of damaged mitochondria with consequent increases in oxidative stress. We identified two molecular bases for this mitophagy deficiency: PINK1/PARKIN impairment and abnormal suppression of macroautophagy. First, strongly downregulated PARKIN and the mitophagic adaptor protein SQSTM1/p62 delays PINK1 activation to impair mitophagy induction after mitochondrial depolarization by CCCP or antimycin A plus oligomycin. Secondly, mTOR is strongly hyper-activated, which globally suppresses macroautophagy induction and the transcriptional expression of proteins critical for autophagosome formation such as ATG7, ATG3 and FOXO1. Notably, inhibition of mTOR complex 1 (mTORC1) and complex 2 (mTORC2) using AZD8055 (AZD) restores autophagy flux, PARKIN/PINK initiation of mitophagy, and the clearance of damaged mitochondria by mitophagy. These results recommend mTORC1-mTORC2 inhibition as a promising candidate therapeutic strategy for Down Syndrome.

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Section: Resultssupporting

confidence: 52%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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mTOR hyperactivation in Down Syndrome underlies deficits in autophagy induction, autophagosome formation, and mitophagy

et al. 2019

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“…Tubers are epileptogenic cortical malformations in TSC. Allana et al showed that both mRNA and protein levels of the DCX protein were higher in TSC nodules than in the control group (43). This result is consistent with our expression of differentially expressed proteins.…”

Section: Discussionsupporting

confidence: 91%

Brain Proteomic Profiling in Intractable Epilepsy Caused by TSC1 Truncating Mutations: A Small Sample Study

Liu

et al. 2020

Front. Neurol.

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Tuberous sclerosis complex (TSC) is a genetic disease characterized by seizures, mental deficiency, and abnormalities of the skin, brain, kidney, heart, and lungs. TSC is inherited in an autosomal dominant manner and is caused by variations in either the TSC1 or TSC2 gene. TSC-related epilepsy (TRE) is the most prevalent and challenging clinical feature of TSC, and more than half of the patients have refractory epilepsy. In clinical practice, we found several patients of intractable epilepsy caused by TSC1 truncating mutations. To study the changes of protein expression in the brain, three cases of diseased brain tissue with TSC1 truncating mutation resected in intractable epilepsy operations and three cases of control brain tissue resected in craniocerebral trauma operations were collected to perform protein spectrum detection, and then the data-independent acquisition (DIA) workflow was used to analyze differentially expressed proteins. As a result, there were 55 up-and 55 down-regulated proteins found in the damaged brain tissue with TSC1 mutation compared to the control. Further bioinformatics analysis revealed that the differentially expressed proteins were mainly concentrated in the synaptic membrane between the patients with TSC and the control. Additionally, TSC1 truncating mutations may affect the pathway of amino acid metabolism. Our study provides a new idea to explore the brain damage mechanism caused by TSC1 mutations.

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“…To filter out low-quality proteins, selected proteins were detected in at least two samples under each condition. DPPs between T24S and T24R cells were identified using a previously reported statistical test 43 . Briefly, log 2- intensities of each protein from T24R cells were compared to those in T24S cells using the Student's t-test and log 2 -median ratio test.…”

Section: Methodsmentioning

confidence: 99%

S-Palmitoylation as a Functional Regulator of Proteins Associated with Cisplatin Resistance in Bladder Cancer

Shahid¹,

Kim²,

Jin³

et al. 2020

Int. J. Biol. Sci.

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Protein S-palmitoylation is a powerful post-translational modification that regulates protein trafficking, localization, turnover, and signal transduction. Palmitoylation controls several important cellular processes, and, if dysregulated, can lead to cancer, cardiovascular disease, and neurological disorders. The role of protein palmitoylation in mediating resistance to systemic cisplatin-based chemotherapies in cancer is currently unknown. This is of particular interest because cisplatin is currently the gold standard of treatment for bladder cancer (BC), and there are no feasible options after resistance is acquired. Using unbiased global proteomic profiling of purified S-palmitoylated peptides combined with intensive bioinformatics analyses, we identified 506 candidate palmitoylated proteins significantly enriched in cisplatin-resistant BC cells. One of these proteins included PD-L1, which is highly palmitoylated in resistant cells. Pharmacological inhibition of fatty acid synthase (FASN) suppressed PD-L1 palmitoylation and expression, which suggests the potential use of FASN-PD-L1-targeted therapeutic strategies in BC patients. Taken together, these results highlight the role of protein palmitoylation in mediating BC chemoresistance.

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Characterization of developmental defects in the forebrain resulting from hyperactivated mTOR signaling by integrative analysis of transcriptomic and proteomic data

Cited by 12 publications

References 45 publications

mTOR hyperactivation in Down Syndrome underlies deficits in autophagy induction, autophagosome formation, and mitophagy

mTOR hyperactivation in Down Syndrome underlies deficits in autophagy induction, autophagosome formation, and mitophagy

Brain Proteomic Profiling in Intractable Epilepsy Caused by TSC1 Truncating Mutations: A Small Sample Study

S-Palmitoylation as a Functional Regulator of Proteins Associated with Cisplatin Resistance in Bladder Cancer

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