TFEB antibody - middle region (P100809_P050)
- Known as:
- TFEB (anti-) - middle region (P100809_P050)
- Catalog number:
- p100809_p050
- Product Quantity:
- USD
- Category:
- -
- Supplier:
- Aviva Systems Biology
- Gene target:
- TFEB antibody - middle region (P100809_P050)
Related genes to: TFEB antibody - middle region (P100809_P050)
- Gene:
- TFEB NIH gene
- Name:
- transcription factor EB
- Previous symbol:
- -
- Synonyms:
- TCFEB, bHLHe35
- Chromosome:
- 6p21.1
- Locus Type:
- gene with protein product
- Date approved:
- 1999-09-20
- Date modifiied:
- 2016-10-05
Related products to: TFEB antibody - middle region (P100809_P050)
Related articles to: TFEB antibody - middle region (P100809_P050)
- Ceritinib, an anaplastic lymphoma kinase (ALK) inhibitor, is associated with cardiovascular adverse events, yet the mechanisms remain incompletely understood. Here, we show that ceritinib impairs left ventricular systolic function in mice and induces cardiomyocyte apoptosis, and identify AKT (Ser473) suppression as a key initiating event. Loss of AKT activity is paralleled by reduced phosphorylation of mTOR (Ser2448) and ULK1 (Ser757), consistent with enhanced autophagy initiation. Concurrently, loss of inhibitory GSK3β (Ser9) phosphorylation correlates with impaired lysosomal function, reflected by disrupted cathepsin D maturation and reduced lysosomal acidification. This mismatch between enhanced autophagy initiation and impaired lysosomal clearance impairs autophagic flux despite preserved autophagosome-lysosome fusion, and causes mitochondrial damage, evidenced by reduced TOMM20 and HSP60 expression and membrane potential loss. Transcriptomic and functional analyses identify AKT2 as a particularly vulnerable isoform in this network. Metformin co-treatment preserves cardiac function and attenuates apoptosis. Mechanistically, metformin increases AMPK (Thr172) phosphorylation and reduces TFEB (Ser122) phosphorylation, restores CTSD maturation, and decreases LC3-II accumulation. These protective effects occur without reversing the suppressed AKT (Ser473) or GSK3β (Ser9) phosphorylation. Together, these findings establish that AKT suppression drives ceritinib cardiotoxicity through autophagic flux impairment and mitochondrial injury, and position AMPK-driven, TFEB-associated lysosomal restoration as a mechanism-based cardioprotective strategy independent of AKT recovery. - Source: PubMed
Publication date: 2026/08/21
Jiang FengFu Huang-XiWang LanPan Ze-ZhengJiang Yan-QiLiu NingChen Xue-QinGao Zi-ZhengWu Wen-TongYan HaoYang Xiao-ChunYang BoHe Qiao-JunLuo Pei-HuaXu Zhi-Fei - The mammalian/mechanistic Target of Rapamycin Complex 1 (mTORC1) orchestrates cell growth and metabolism in response to diverse extracellular and intracellular cues. mTORC1 phosphorylates a broad range of substrates, each of which plays important physiological roles. Emerging evidence suggests that mTORC1 can respond to upstream signals in a nuanced manner, enabling differential regulation of individual substrates and, consequently, specific downstream biological processes. Phosphorylation of non-canonical mTORC1 substrates, such as the lysosome biogenesis regulator transcription factor EB (TFEB), can be regulated independently of phosphorylation of canonical substrates. However, the nature of signals that determine the signaling selectivity of mTORC1 remains incompletely understood. Here, we studied mTORC1 regulation by G protein-coupled receptors (GPCRs). We found that phosphorylation of TFEB responds to GPCRs differently, compared to canonical mTORC1 substrates controlling protein synthesis such as S6K1 and 4EBP1. In particular, the muscarinic acetylcholine receptor M5 (M5R) promoted phosphorylation of S6K1 and 4EBP1, while triggering TFEB dephosphorylation. Consequently, M5R stimulated protein synthesis without inhibiting lysosome biogenesis. mTORC1 can thus separately regulate anabolic and catabolic processes under the control of M5R. This study highlights the importance of reassessing the effects of GPCRs on mTORC1 by concurrently monitoring individual substrates, a critical consideration to be made when evaluating GPCR ligands as therapeutic agents targeting the mTORC1 pathway. - Source: PubMed
Publication date: 2026/08/19
Atkinson Samuel JNegoita FlorentinaIoi YuichiroRitchie William VincentThompson KyleGardner MaxAshdown Peter THellberg KristinaTakahara TerunaoSakamoto KeiThompson DawnHislop James NHatakeyama Riko - Parkinson's disease (PD) is increasingly recognized as a disorder of glial dysfunction, wherein astrocytes transition from homeostatic supporters to active drivers of neurodegeneration. This review synthesizes recent evidence to propose a novel dual-pathway failure model in which internalized alpha-synuclein orchestrates a self-amplifying cycle of astrocytic toxicity. Pathological alpha-synuclein simultaneously suppresses key cytoprotective systems, the Nrf2-mediated antioxidant response and TFEB-regulated autophagy-lysosomal degradation, while hyperactivating neuroinflammatory signaling via NF-κB/MAPK and the recently implicated cGAS-STING axis, triggered by mitochondrial DNA release. This imbalance fosters chronic oxidative stress, proteostatic collapse, and sustained neuroinflammation. Ferroptosis, a form of necrotic cell death characterized by iron dependency and lipid peroxidation, may represent a likely downstream consequence of astrocytic death when protective failure (Nrf2/TFEB suppression) overlaps with toxic activation (cGAS-STING/NF-κB signaling) and disturbances in iron and lipid homeostasis. The concurrent failure of antioxidant defenses and the buildup of labile iron and peroxidizable lipids could establish a conducive environment for ferroptotic membrane rupture, potentially resulting in secondary neuronal damage. This gliocentric model reframes PD pathogenesis as a feed-forward loop of neurotoxicity originating in astrocytic reprogramming. Therapeutically, breaking this cycle via STING inhibition, Nrf2/TFEB activation, and anti-ferroptotic agents represents a promising but still experimental avenue for intervention aimed at restoring astrocyte homeostasis and potentially halting neurodegeneration. However, it is critical to note that the evidence supporting these approaches is derived almost exclusively from preclinical models, with no approved therapies targeting these astrocytic pathways currently available for PD patients. - Source: PubMed
Publication date: 2026/08/19
Abdelaziz Ahmed M - Transcription factors often exhibit a striking paradox: they function as tumor suppressors in one context and promote oncogenesis in another. The underlying mechanisms of this context dependence have remained elusive. We propose a novel conceptual framework, systemic redox switching, to resolve this paradox. Based on our research on upstream stimulatory factor 2 (USF2) and convergent observations on other factors, our model suggests that redox regulation is network-embedded rather than driven by discrete cysteine switches. We propose that transcription factors occupy distinct regulatory regimes (homeostatic, adaptive, and survival states) which are connected by threshold-like, hysteretic transitions. Beyond classical graded input-output views, this framework explicitly posits discrete, hysteretic regime transitions at the transcriptional-network level and links them to a minimal dynamical model of the USF2-TFEB-NRF2-redox motif. These transitions convert continuous redox inputs into distinct changes in promoter occupancy and transcriptional programs. USF2 exemplifies a kinase-integrated, non-canonical switch that decodes mitochondrial and autophagy signals via phosphorylation (e.g., Ser155) and context-dependent cooperation with NRF2 and HIFs. Extending this logic to diverse archetypes (NRF2, HIFs, FOXOs, c-MYC, and AHR) demonstrates the framework's generalizability. The model is experimentally tractable; targeted perturbations of primary sensing modules (e.g., KEAP1 mutation, PHD inhibition, or USF2 phosphorylation disruption) should predictably alter regime transitions. By reframing paradoxical behaviors as controlled state transitions, this framework provides a unifying, network-level understanding with direct implications for targeting therapies in cancer, metabolic diseases, and age-related pathologies. - Source: PubMed
Publication date: 2026/08/12
Dimova Elitsa YKietzmann Thomas - Macroautophagy (MA) and chaperone-mediated autophagy (CMA) are lysosomal degradation pathways with context-dependent roles in cancer. However, how MA- and CMA-associated transcriptional states jointly relate to cancer molecular features and drug responses remains unclear. Here, we developed a transcriptome-based framework integrating MA- and CMA-associated gene signatures to define relative MA and CMA states across cancer types. These states were associated with distinct patterns of genomic instability, oncogenic signaling, immune features, and pharmacogenomic profiles. In pooled cancer cell-line analyses, MA CMA states were associated with relative resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs), whereas MA CMA states showed greater sensitivity, nominating an autophagy-associated pharmacological pattern for mechanistic investigation. Using KRAS-mutant pancreatic cancer cells as an autophagy-dependent, therapy-resistant model, we found that depletion enhanced sensitivity to EGFR-TKIs in an MA-dependent manner. All-trans retinoic acid (ATRA), a pleiotropic retinoid that modulated CMA-related activity in this system, phenocopied key effects of genetic CMA suppression and potentiated sensitivity to EGFR-TKIs. CMA suppression was associated with increased autophagic flux, TFEB nuclear localization, and ULK1 phosphorylation changes consistent with MA activation. Moreover, transcriptomic analysis reveals that CMA suppression sensitizes cancer cells to EGFR-TKIs at least partially through downregulation of SEMA6D. SEMA6D depletion enhanced autophagic flux, increased lysosomal capacity, and partially contributed to the response to combined EGFR-TKI and ATRA treatment. In PANC-1 xenografts, ATRA potentiated EGFR-TKI-mediated tumor suppression without significant toxicity. Together, these findings establish a transcriptome-based MA-CMA framework for prioritizing context-dependent autophagy-associated vulnerabilities and provide focused mechanistic support for MA-CMA crosstalk in KRAS-mutant pancreatic cancer models. ACTB: actin beta; ANOVA: analysis of variance; ARI: adjusted rand index; ATRA: all-trans retinoic acid; BLCA: bladder urothelial carcinoma; BSA: bovine serum albumin; CMA: chaperone-mediated autophagy; CNV: copy number variation; COAD: colon adenocarcinoma; DEG: differentially expressed gene; DMEM: dulbecco's modified eagle medium; DMSO: dimethyl sulfoxide; EBSS: Earle's balanced salt solution; EGFR: epidermal growth factor receptor; EGFR-TKI: EGFR tyrosine kinase inhibitor; EV: empty vector; FBS: fetal bovine serum; FDR: false discovery rate; FM: full medium; HCQ: hydroxychloroquine; HNSC: head and neck squamous cell carcinoma; H&E: hematoxylin and eosin; i.p.: intraperitoneally; HRD: homologous recombination deficiency; HSPA8/HSC70: heat shock protein family A (Hsp70) member 8; KIRC: kidney renal clear cell carcinoma; LAMP2A: lysosome associated membrane protein 2A; LGG: lower-grade glioma; LOH: loss of heterozygosity; LUAD: lung adenocarcinoma; LUSC: lung squamous cell carcinoma; MA: macroautophagy; MSI: microsatellite instability; MSigDB: molecular signatures database; OR: odds ratio; PDAC: pancreatic ductal adenocarcinoma; qRT-PCR: quantitative real-time PCR; SEMA6D: semaphorin 6D; sgRNA: single-guide RNA; siRNA: small interfering RNA; SKCM: skin cutaneous melanoma; SMD: standardized mean differences; SNV: single-nucleotide variant; SQSTM1/p62: sequestosome 1; ssGSEA: single-sample gene set enrichment analysis; STAD: stomach adenocarcinoma; TCGA: the cancer genome atlas; TMB: tumor mutation burden; TPM: transcripts per million. - Source: PubMed
Publication date: 2026/08/19
Feng JilingZeng YuWu HaoFeng YuanlongLuo ShengnanDong ShuxianLi Shengli