A5033743612- Autophagy in Disease and Therapy
- Epigenetics and DNA Methylation
- Cancer, Hypoxia, and Metabolism
- Renal cell carcinoma treatment
- Ubiquitin and proteasome pathways
- PI3K/AKT/mTOR signaling in cancer
- Mitochondrial Function and Pathology
- Cancer-related gene regulation
- Sirtuins and Resveratrol in Medicine
- Cancer Genomics and Diagnostics
- ATP Synthase and ATPases Research
- Endoplasmic Reticulum Stress and Disease
- MicroRNA in disease regulation
- Phagocytosis and Immune Regulation
- Renal and related cancers
- RNA modifications and cancer
- Cannabis and Cannabinoid Research
- High Altitude and Hypoxia
- Lipid metabolism and biosynthesis
- Peptidase Inhibition and Analysis
- Occupational and environmental lung diseases
- Neuroblastoma Research and Treatments
- Protein Degradation and Inhibitors
- Hippo pathway signaling and YAP/TAZ
- Cell death mechanisms and regulation
Essen University Hospital
2019-2025
University of Duisburg-Essen
2021-2022
German Cancer Research Center
2020
Heidelberg University
2018-2020
Deutschen Konsortium für Translationale Krebsforschung
2019
The University of Texas Southwestern Medical Center
2010-2018
DKFZ-ZMBH Alliance
2018
Harold C. Simmons Comprehensive Cancer Center
2010
The master regulator of lysosome biogenesis, TFEB, is regulated by MTORC1 through phosphorylation at S211, and a S211A mutation increases nuclear localization. However, TFEBS211A localizes diffusely in both cytoplasm nucleus and, as we show, retains regulation MTORC1. Here, report that endogenous TFEB phosphorylated S122 an MTORC1-dependent manner, vitro recombinant MTOR, important for Specifically, localization following inhibition blocked S122D (despite S211 dephosphorylation)....
Significance Approximately 20% of breast cancers have amplification a cancer-causing signaling molecule known as human epidermal growth factor receptor 2 (HER2). Decreased mRNA expression the autophagy gene, beclin 1/BECN1 , increases risk HER2-positive cancer. However, role Beclin 1-dependent in regulating HER2-mediated tumorigenesis is unknown. Here, we show that mutation Becn1 basal prevents mice and inhibition cultured cells. Furthermore, treatment with cell-penetrating,...
mTORC1 is a critical regulator of cell growth that integrates multiple signals and deregulated in cancer. We previously reported regulation by hypoxia involves Redd1 the Tsc1/Tsc2 complex. Here we show induction tissue dependent are relayed to through different pathways tissue-specific manner. In liver, restricted centrilobular area, primary hepatocytes, inhibition independent Redd1. Furthermore, Arnt (Hif-1β) similarly dispensable. Hypoxia signaling hepatocytes Lkb1, AMP-activated protein...
REDD1 is a conserved stress-response protein that regulates mTORC1, critical regulator of cell growth and proliferation implicated in cancer. induced by hypoxia, overexpression sufficient to inhibit mTORC1. mTORC1 regulated the small GTPase Rheb, which turn GTPase-activating complex, TSC1/TSC2. induced-mTORC1 inhibition requires TSC1/TSC2 has been proposed act directly binding sequestering 14-3-3 proteins away from TSC2 leading TSC2-dependent Structure/function analyses have led us identify...
Abstract GRB2 is an adaptor protein of HER2 (and several other tyrosine kinases), which we identified as a novel BECN1 (Beclin 1) interacting partner. co-immunoprecipitated with in breast cancer cell lines and regulates autophagy through mechanism involving the modulation class III PI3Kinase VPS34 activity. In ovo studies CAM (Chicken Chorioallantoic Membrane) model indicated that knockdown, well overexpression loss-of-function mutants (Y52A S86A-R88A) compromised tumor growth. These...
The KIT/c-KIT proto-oncogene is frequently over-expressed in Merkel cell carcinoma (MCC), an aggressive skin cancer commonly caused by polyomavirus (MCPyV). Here, we demonstrated that truncated MCPyV-encoded large T-antigen (LT) suppressed macroautophagy/autophagy stabilizing and sequestering KIT the paranuclear compartment via binding VPS39. engaged with phosphorylated BECN1, thereby enhancing its association BCL2 while diminishing interaction PIK3C3 complex. This process ultimately...
Abstract Oncogenic KRAS mutations are encountered in more than 90% of pancreatic ductal adenocarcinomas. MEK inhibition has failed to procure any clinical benefits mutant RAS-driven cancers including adenocarcinoma (PDAC). To identify potential resistance mechanisms underlying inhibitor (MEKi) PDAC, we investigated lysosomal drug accumulation PDAC models both vitro and vivo. Mouse human cell lines as well xenografts treated with the trametinib or refametinib led an enhanced expression...
Cancer bioenergetics fuel processes necessary to maintain viability and growth under stress conditions. We hypothesized that cancer metabolism supports the repair of radiation-induced DNA double-stranded breaks (DSBs). combined systematic collection metabolic radiobiological data from a panel irradiated cell lines with mathematical modeling identified common response impact on DSB kinetics, including mitochondrial shutdown followed by compensatory glycolysis resumption function. Combining...
Depending on context and tumor stage, deregulation of autophagy can either suppress tumorigenesis or promote chemoresistance survival. Histone deacetylases (HDACs) modulate autophagy; however, the exact mechanisms are not fully understood. Here, we analyze effects broad-spectrum HDAC inhibitors (HDACi) panobinostat vorinostat transcriptional regulation with respect to transcription factor activity (Transcription EB—TFEB, forkhead boxO—FOXO) autophagic flux in neuroblastoma cells. In...
Uncontrolled proliferation and altered metabolic reprogramming are hallmarks of cancer. Active glycolysis glutaminolysis characteristic features these required for tumorigenesis. A fine balance between cancer metabolism autophagy is a prerequisite homeostasis within cells. Here we show that glutamate pyruvate transaminase 2 (GPT2), which serves as pivot glutaminolysis, highly upregulated in aggressive breast cancers, particularly the triple-negative subtype. Abrogation this enzyme results...
Synonymous mutations are generally disregarded by genomic analyses because they considered non-pathogenic. We identified and characterized a somatic synonymous mutation in the epigenetic modifier tumor suppressor BAP1, resulting exon skipping complete protein inactivation. This radically altered prognosis of clear-cell renal cell carcinoma patient from The Cancer Genome Atlas (TCGA) with PBRM1 (a predictor biomarker for positive responses to immune checkpoint inhibitors) good (an estimated...
Malignant pleural mesothelioma (MPM) is a rare type of cancer with grim prognosis. So far, no targetable oncogenic mutation was identified in MPM and biomarkers predictive value toward drug sensitivity or resistance are also lacking. Nintedanib (BIBF1120) small-molecule tyrosine kinase inhibitor that showed promising efficacy preclinically phase II trial as an angiogenesis combined chemotherapy. However, the extended III failed. In this study, we investigated effect nintedanib on one its...
Abstract The HGF/c-Met signaling pathway facilitates the initiation, progression, and metastasis of hepatocellular carcinoma (HCC). c-Met activation, however, is complex not solely dependent on HGF, hindering targeted therapy development. This study identifies a critical oncogenic role for HHLA2, B7 family member, in HCC highlights its potential as therapeutic target. We demonstrate that HHLA2 directly interacts with activates through N-glycosylation, triggering sustained promoting...
BECN1 (BCL2 interacting myosin like coiled protein) is a major regulator of autophagy and haploinsufficient tumor suppressor. binds to multiple proteins it part at least two different class III phosphatidylinositol (PI) 3 Kinase (PI3KC3) complexes that regulate endocytic trafficking through the biosynthesis phosphatidylinositol-3-phosphate. activity PI3KC3 are regulated by post-translational modifications and/or subcellular localization. We recently discovered GRB2 (growth factor receptor...
Autophagy is an intracellular degradation process that maintains the cellular homeostasis and it regulated in multiple ways, both health disease. Assessment of autophagic flux cells important approach for understanding function autophagy biological contexts. Here, we describe a new tool qualitative quantitative determination using dual lentiviral reporter system generates fusion HiBiT-GFP-LC3B protein suitable generating stable cell lines.
Review on DDIT4 (DNA-damage-inducible transcript 4), with data DNA, the protein encoded, and where gene is implicated.
Autophagy is a dynamic process that can be monitored in multiple ways, both vitro and vivo. Studies mice are widely used tool to understand diseases conditions where autophagy plays role, therefore autophagic flux measurement tissues of rodent models utmost importance. Here, we present some assays successfully determining the status mammary gland as well xenografts.