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2022 ◽  
Author(s):  
Kajal Rajput ◽  
Mohammad Nafees Ansari ◽  
Somesh Kumar Jha ◽  
Pankaj Sharma ◽  
Sudeshna Datta ◽  
...  

Sphingolipid and ganglioside metabolic pathways are crucial components of cell signalling, having established roles in tumor cell proliferation, invasion, and migration. However, regulatory mechanisms controlling sphingolipid and ganglioside synthesis in mammalian cells is less known. Here, we show that RICTOR, the regulatory subunit of mTORC2, regulates the synthesis of sphingolipids and gangliosides in Luminal breast cancer-specific MCF-7 cells through transcriptional and epigenetic mechanisms. RICTOR regulates glucosylceramide levels by modulating the expression of UDP-Glucose Ceramide Glucosyl transferase (UGCG). We identify Zinc Finger protein X-linked (ZFX) as a RICTOR-responsive transcription factor whose recruitment to the UGCG promoter is regulated by DNA methyltransferases and histone demethylase (KDM5A) that are known AKT substrates. We further demonstrate that RICTOR regulates the synthesis of GD3 gangliosides through ZFX and UGCG, and triggers the activation of the EGFR signalling pathway, thereby promoting tumor growth. In line with our findings in cell culture and mice models, we observe an elevated expression of RICTOR, ZFX, and UGCG in Indian Luminal breast cancer patient samples, and in TCGA and METABRIC datasets. Together, we establish a key regulatory circuit, RICTOR-AKT-ZFX-UGCG-Ganglioside-EGFR-AKT, and elucidate its contribution to breast cancer progression.


2022 ◽  
Author(s):  
Xingyuan Chen ◽  
Zhanhui Ye ◽  
Kequan Chen ◽  
Jiahui Xu ◽  
Liangying Ye ◽  
...  

Abstract Background The genetic mechanism of glucose metabolism has not been elucidated in nonalcoholic steatohepatitis (NASH), and many genes are took part in glucose metabolism of NASH. In this study, we used the weighted gene co-expression network analysis (WGCNA) to find the key genes associated with glucose metabolism; Methods Data sets GSE96971 and GSE89632 from Gene Expression Omnibus (GEO) were analyzed by WGCNA. We screened the Hub gene from the GSE96971 dataset, and the selected Hub genes were verified by GSE89632 dataset. We then analyzed the dataset using the Gene Ontology (GO) term enrichment and the Kyoto Encyclopedia of Genome (KEGG) path analysis. Expression levels of the hub genes are assessed by qPCR analysis. The function of hub genes was verified by Nile Red staining and relative glucose consumption detection; Results The hub genes are mannosidase beta like (MANBAL), myc proto-oncogene protein (MYC), caspase 4 (CASP4), CDK5 regulatory subunit associated protein 3 (CDK5RAP3) and ZFP36 ring finger protein (ZFP36) in the datasets GSE96971 and the GSE89632. Further, these genes are mainly involved in the integral component of membrane and plasma membrane, the PI3K-AKT signaling pathway and the olfactory transduction according to the GO and KEGG results. These hub genes were significantly up-regulated in the palmitic acid (PA) cell model and methionine-choline-deficient medium (MCD) cell model. After knocking out the hub genes in PA model and the MCD model of NASH, relative glucose consumption was increased and lipid deposition was reduced compared with the control group; Conclusions MANBAL, MYC, CASP4, CDK5RAP3 and ZFP36 are elevated and involved in the pathogenesis of NASH. Further research on these genes are warranted.


2022 ◽  
Vol 20 (1) ◽  
Author(s):  
Guy Nadel ◽  
Zhong Yao ◽  
Ehud Wainstein ◽  
Izel Cohen ◽  
Ido Ben-Ami ◽  
...  

Abstract Background G protein-coupled receptors (GPCRs) usually regulate cellular processes via activation of intracellular signaling pathways. However, we have previously shown that in several cell lines, GqPCRs induce immediate inactivation of the AKT pathway, which leads to JNK-dependent apoptosis. This apoptosis-inducing AKT inactivation is essential for physiological functions of several GqPCRs, including those for PGF2α and GnRH. Methods Here we used kinase activity assays of PI3K and followed phosphorylation state of proteins using specific antibodies. In addition, we used coimmunoprecipitation and proximity ligation assays to follow protein–protein interactions. Apoptosis was detected by TUNEL assay and PARP1 cleavage. Results We identified the mechanism that allows the unique stimulated inactivation of AKT and show that the main regulator of this process is the phosphatase PP2A, operating with the non-canonical regulatory subunit IGBP1. In resting cells, an IGBP1-PP2Ac dimer binds to PI3K, dephosphorylates the inhibitory pSer608-p85 of PI3K and thus maintains its high basal activity. Upon GqPCR activation, the PP2Ac-IGBP1 dimer detaches from PI3K and thus allows the inhibitory dephosphorylation. At this stage, the free PP2Ac together with IGBP1 and PP2Aa binds to AKT, causing its dephosphorylation and inactivation. Conclusion Our results show a stimulated shift of PP2Ac from PI3K to AKT termed “PP2A switch” that represses the PI3K/AKT pathway, providing a unique mechanism of GPCR-stimulated dephosphorylation.


2022 ◽  
Vol 12 (1) ◽  
Author(s):  
Ling Li ◽  
Jeremy Thompson ◽  
Ying Hu ◽  
Edward J. Lesnefsky ◽  
Belinda Willard ◽  
...  

AbstractCalpain 1 and 2 (CPN1/2) are calcium-dependent cysteine proteases that exist in cytosol and mitochondria. Pharmacologic inhibition of CPN1/2 decreases cardiac injury during ischemia (ISC)–reperfusion (REP) by improving mitochondrial function. However, the protein targets of CPN1/2 activation during ISC–REP are unclear. CPN1/2 include a large subunit and a small regulatory subunit 1 (CPNS1). Genetic deletion of CPNS1 eliminates the activities of both CPN1 and CPN2. Conditional cardiomyocyte specific CPNS1 deletion mice were used in the present study to clarify the role of CPN1/2 activation in mitochondrial damage during ISC–REP with an emphasis on identifying the potential protein targets of CPN1/2. Isolated hearts from wild type (WT) or CPNS1 deletion mice underwent 25 min in vitro global ISC and 30 min REP. Deletion of CPNS1 led to decreased cytosolic and mitochondrial calpain 1 activation compared to WT. Cardiac injury was decreased in CPNS1 deletion mice following ISC–REP as shown by the decreased infarct size compared to WT. Compared to WT, mitochondrial function was improved in CPNS1 deletion mice following ischemia–reperfusion as shown by the improved oxidative phosphorylation and decreased susceptibility to mitochondrial permeability transition pore opening. H2O2 generation was also decreased in mitochondria from deletion mice following ISC–REP compared to WT. Deletion of CPNS1 also resulted in less cytochrome c and truncated apoptosis inducing factor (tAIF) release from mitochondria. Proteomic analysis of the isolated mitochondria showed that deletion of CPNS1 increased the content of proteins functioning in regulation of mitochondrial calcium homeostasis (paraplegin and sarcalumenin) and complex III activity. These results suggest that activation of CPN1 increases cardiac injury during ischemia–reperfusion by impairing mitochondrial function and triggering cytochrome c and tAIF release from mitochondria into cytosol.


2022 ◽  
Vol 12 ◽  
Author(s):  
Qiaoli Zeng ◽  
Dehua Zou ◽  
Shanshan Gu ◽  
Fengqiong Han ◽  
Shilin Cao ◽  
...  

Background:CDK5 regulatory subunit associated protein 1 like 1 (CDKAL1) is a major pathogenesis-related protein for type 2 diabetes mellitus (T2DM). Recently, some studies have investigated the association of CDKAL1 susceptibility variants, including rs4712523, rs4712524, and rs9460546 with T2DM. However, the results were inconsistent. This study aimed to evaluate the association of CDKAL1 variants and T2DM patients.Methods: A comprehensive meta-analysis was performed to assess the association between CDKAL1 SNPs and T2DM among dominant, recessive, additive, and allele models.Results: We investigated these three CDKAL1 variants to identify T2DM risk. Our findings were as follows: rs4712523 was associated with an increased risk of T2DM for the allele model (G vs A: OR = 1.172; 95% CI: 1.103–1.244; p < 0.001) and dominant model (GG + AG vs AA: OR = 1.464; 95% CI: 1.073–1.996; p = 0.016); rs4712524 was significantly associated with an increased risk of T2DM for the allele model (G vs A: OR = 1.146; 95% CI: 1.056–1.245; p = 0.001), additive model (GG vs AA: OR = 1.455; 95% CI: 1.265–1.673; p < 0.001) recessive model (GG vs AA + AG: OR = 1.343; 95% CI: 1.187–1.518; p < 0.001) and dominant model (GG + AG vs AA: OR = 1.221; 95% CI: 1.155–1.292; p < 0.001); and rs9460546 was associated with an increased risk of T2DM for the allele model (G vs T: OR = 1.215; 95% CI: 1.167–1.264; p = 0.023). The same results were found in the East Asian subgroup for the allele model.Conclusions: Our findings suggest that CDKAL1 polymorphisms (rs4712523, rs4712524, and rs9460546) are significantly associated with T2DM.


2022 ◽  
Vol 23 (1) ◽  
pp. 507
Author(s):  
Hikari Watanabe ◽  
Chika Yoshida ◽  
Masafumi Hidaka ◽  
Tomohisa Ogawa ◽  
Taisuke Tomita ◽  
...  

Amyloid beta peptides (Aβs) are generated from amyloid precursor protein (APP) through multiple cleavage steps mediated by γ-secretase, including endoproteolysis and carboxypeptidase-like trimming. The generation of neurotoxic Aβ42/43 species is enhanced by familial Alzheimer’s disease (FAD) mutations within the catalytic subunit of γ-secretase, presenilin 1 (PS1). FAD mutations of PS1 cause partial loss-of-function and decrease the cleavage activity. Activating mutations, which have the opposite effect of FAD mutations, are important for studying Aβ production. Aph1 is a regulatory subunit of γ-secretase; it is presumed to function as a scaffold of the complex. In this study, we identified Aph1 mutations that are active in the absence of nicastrin (NCT) using a yeast γ-secretase assay. We analyzed these Aph1 mutations in the presence of NCT; we found that the L30F/T164A mutation is activating. When introduced in mouse embryonic fibroblasts, the mutation enhanced cleavage. The Aph1 mutants produced more short and long Aβs than did the wild-type Aph1, without an apparent modulatory function. The mutants did not change the amount of γ-secretase complex, suggesting that L30F/T164A enhances catalytic activity. Our results provide insights into the regulatory function of Aph1 in γ-secretase activity.


2021 ◽  
Author(s):  
Siffat Ullah Khan ◽  
Yanxiao Zheng ◽  
Zaid Chachar ◽  
Xuhuan Zhang ◽  
Guyi Zhou ◽  
...  

Abstract Drought is one of the most critical environmental factors constraining corn production especially when it occurs during flowering, resulting in serious yield losses. In this study, anthesis to silk interval (ASI), plant height (PH), and ear biomass at the silking date (EBM) of 279 inbred lines were evaluated under water-stress (WS) and well-water (WW) field conditions for three consecutive years. Averagely, ASI was extended by 25.96%, ear biomass was decreased by 17.54%, and the PH was reduced by 12.47% under drought stress conditions. Genome wide association studies (GWAS) were carried out using phenotypic values under WS, WW and drought-tolerance index (WS-WW or WS/WW) applying mixed linear model controlling both population structure and relative kinship. Totally, 71, 159, and 21 SNPs were significantly (P < 10-5) associated with ASI, ear biomass, and PH, respectively. Candidate genes encoding ARABIDILLO 1 protein, glycoprotein, Tic22-like and Zinc finger family protein for ASI, and 26S proteasome non-ATPase regulatory subunit-9 for EBM, were identified under both WW and WS conditions. Pyridoxal phosphate transferase was associated with EBM under drought stress treatment in consecutive two years. Furthermore, most candidate genes were evidenced to be drought responsive in the association panel. Meanwhile, the favourable/drought tolerance haplotypes were identified based on haplotype analysis. These findings provide insights into the genetic basis of drought tolerance at the flowering stage especially for the female inflorescence development and will facilitate high drought tolerant maize breeding.


2021 ◽  
Vol 23 (1) ◽  
pp. 289
Author(s):  
Ya-Nan Gao ◽  
Song-Li Li ◽  
Xue Yang ◽  
Jia-Qi Wang ◽  
Nan Zheng

Aflatoxin M1 (AFM1), the only toxin with maximum residue levels in milk, has adverse effects on the intestinal barrier, resulting in intestinal inflammatory disease. Lactoferrin (LF), one of the important bioactive proteins in milk, performs multiple biological functions, but knowledge of the protective effects of LF on the compromised intestinal barrier induced by AFM1 has not been investigated. In the present study, results using Balb/C mice and differentiated Caco-2 cells showed that LF intervention decreased AFM1-induced increased intestinal permeability, improved the protein expression of claudin-3, occludin and ZO-1, and repaired the injured intestinal barrier. The transcriptome and proteome were used to clarify the underlying mechanisms. It was found that LF reduced the intestinal barrier dysfunction caused by AFM1 and was associated with intestinal cell survival related pathways, such as cell cycle, apoptosis and MAPK signaling pathway and intestinal integrity related pathways including endocytosis, tight junction, adherens junction and gap junction. The cross-omics analysis suggested that insulin receptor (INSR), cytoplasmic FMR1 interacting protein 2 (CYFIP2), dedicator of cytokinesis 1 (DOCK1) and ribonucleotide reductase regulatory subunit M2 (RRM2) were the potential key regulators as LF repaired the compromised intestinal barrier. These findings indicated that LF may be an alternative treatment for the compromised intestinal barrier induced by AFM1.


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