☆ 4.7 Review

Protein Quality Control in Glioblastoma: A Review of the Current Literature with New Perspectives on Therapeutic Targets

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (2022)

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Review Oncology

Diagnostic, therapeutic, and prognostic implications of the 2021 World Health Organization classification of tumors of the central nervous system

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Summary: The 2016 revised WHO classification of CNS tumors incorporated molecular features with histologic grading, revolutionizing oncologists' understanding of primary brain and spinal cord tumors. The 2021 revised edition further integrates molecular alterations, updating the pathophysiology understanding of these diseases.

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Review Oncology

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Summary: This article reviews new strategies and attempts to treat patients with unMGMT GBM, including radiotherapy, chemotherapy, targeted therapy, and immunotherapy. The results of the studies show that individualized treatment for different patient subgroups can achieve better therapeutic outcomes and prolong survival.

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Resensitising proteasome inhibitor-resistant myeloma with sphingosine kinase 2 inhibition

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Summary: The introduction of the proteasome inhibitor bortezomib has improved patient survival in myeloma, but acquired resistance remains a challenge. Researchers have found that inhibiting sphingolipid metabolism can resensitize bortezomib-resistant myeloma, and this approach also works with other proteasome inhibitors like carfilzomib.

NEOPLASIA (2022)

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Review Oncology

The Role of Macroautophagy and Chaperone-Mediated Autophagy in the Pathogenesis and Management of Hepatocellular Carcinoma

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Summary: Hepatocellular carcinoma is a global health problem with limited treatment options, and autophagy plays a complex role in its development. Understanding the relationship between autophagy and HCC is crucial for effective management of this cancer.

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Identification of a Nomogram with an Autophagy-Related Risk Signature for Survival Prediction in Patients with Glioma

Xiaofeng Fu et al.

Summary: This study constructed a novel and reliable autophagy-related risk signature and verified it as a satisfactory prognostic marker. The nomogram model could provide a reference for individually predicting the prognosis for each patient with glioma and promoting the selection of optimal treatment.

INTERNATIONAL JOURNAL OF GENERAL MEDICINE (2022)

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Article Biochemistry & Molecular Biology

BAG3 is a negative regulator of ciliogenesis in glioblastoma and triple-negative breast cancer cells

Benedikt Linder et al.

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JOURNAL OF CELLULAR BIOCHEMISTRY (2022)

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Review Biochemistry & Molecular Biology

The role of Bag3 in cell signaling

Michael Y. Sherman et al.

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Pharmacological inhibition of BAG3-HSP70 with the proposed cancer therapeutic JG-98 is toxic for cardiomyocytes

Thomas G. Martin et al.

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JOURNAL OF CELLULAR BIOCHEMISTRY (2022)

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An allosteric inhibitor of bacterial Hsp70 chaperone potentiates antibiotics and mitigates resistance

Jordan Hosfelt et al.

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Bcl2-associated athanogene 4 promotes the invasion and metastasis of gastric cancer cells by activating the PI3K/AKT/NF-κB/ZEB1 axis

Lei Jiang et al.

Summary: BAG4 has been found to be overexpressed in gastric cancer tissues compared to normal tissues, and its elevated expression is associated with advanced tumor characteristics and poor patient outcomes. Mechanistically, BAG4 promotes invasion and metastasis of gastric cancer cells by activating the PI3K/AKT/NF-kappa B/ZEB1 axis to induce epithelial-mesenchymal transition.

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The lysosome as an imperative regulator of autophagy and cell death

Kewal Kumar Mahapatra et al.

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Review Biochemistry & Molecular Biology

Molecular Mechanisms of Treatment Resistance in Glioblastoma

Alexander Ou et al.

Summary: Glioblastoma is the most common malignant primary brain tumor in adults and is almost invariably fatal. The challenges of treating glioblastoma include the blood-brain barrier, tumoral heterogeneity, and immunosuppressive microenvironment.

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (2021)

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Chaperone-mediated autophagy sustains haematopoietic stem-cell function

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Summary: Activation of hematopoietic stem cells involves molecular adaptations, with Chaperone-Mediated Autophagy (CMA) playing a role in sustaining HSC function and declining with age. Restoring old HSC functionality through CMA activation suggests it may be a promising therapeutic target for conditions like aging or stem-cell transplantation.

NATURE (2021)

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Review Biochemistry & Molecular Biology

Prognostic and Predictive Biomarkers in Gliomas

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Summary: The latest research on prognostic and predictive biomarkers in gliomas has been compiled, highlighting the importance of prognostic markers in adult and pediatric patients and the clinical significance in predicting treatment responses. Further work is needed to implement novel technologies such as liquid biopsies in clinical practice.

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (2021)

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Proteasome Inhibitors and Their Pharmacokinetics, Pharmacodynamics, and Metabolism

Jinhai Wang et al.

Summary: The proteasome plays a crucial role in tumor and immune cell biology, serving as a therapeutic target for drug development. Various inhibitors have been approved for the treatment of multiple myeloma, with ongoing development of selective immunoproteasome inhibitors for autoimmune diseases. Researchers compare the pharmacokinetics, pharmacodynamics, and metabolism of these compounds, highlighting the distinct metabolism pathway of peptide epoxyketones as a favorable property for chronic conditions.

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (2021)

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Circ_0008305-mediated miR-660/BAG5 axis contributes to hepatocellular carcinoma tumorigenesis

Fuguo Yan et al.

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CANCER MEDICINE (2021)

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Natural compounds in the regulation of proteostatic pathways: An invincible artillery against stress, ageing, and diseases

Arun Upadhyay

Summary: The coordination of molecular mechanisms within cells is crucial for cellular function, and modulating the protein quality control system can alleviate cellular protein load and mitigate pathological conditions. Natural medicine and small molecule-based therapies have been shown to effectively restore cellular protein homeostasis for combating disease conditions.

ACTA PHARMACEUTICA SINICA B (2021)

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Recurrent Glioblastoma: From Molecular Landscape to New Treatment Perspectives

Cristina Birzu et al.

Summary: Glioblastoma is the most common and aggressive primary brain cancer in adults. Despite standard treatments including surgery, radiotherapy, and chemotherapy, prognosis remains poor with relapse being common. New treatment options such as immunotherapy and targeted therapy have shown promise in recent years for recurrent cases.

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Expression of BAG1 is associated with prognosis in kidney renal clear cell carcinoma based on bioinformatics

Hongrong Wu et al.

Summary: BAG1 expression levels in KIRC were found to be lower in tumor samples compared to normal tissues. Low BAG1 expression was associated with various clinicopathological factors, while high BAG1 expression was linked to longer survival in KIRC patients. The study suggests that BAG1 may serve as a potential prognostic marker and therapeutic target in KIRC.

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PRMT6 deficiency induces autophagy in hostile microenvironments of hepatocellular carcinoma tumors by regulating BAG5-associated HSC70 stability

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Summary: Autophagy plays a critical role in cancer cells such as hepatocellular carcinoma (HCC), and deficiency of the post-translational modification enzyme PRMT6 promotes autophagy induction in HCC under stress conditions. PRMT6 interacts with and methylates BAG5 to regulate HSC70 stability, influencing autophagy in HCC cells. Targeting BAG5 may be a promising strategy in HCC treatment to suppress autophagy and enhance sensitivity to sorafenib.

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Romain Ragimbeau et al.

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Pathway signatures derived from on-treatment tumor specimens predict response to anti-PD1 blockade in metastatic melanoma

Kuang Du et al.

Summary: Researchers have developed pathway-based signatures using transcriptomic data and clinical information to accurately predict responses to anti-PD1 therapy in melanoma, with the PASS-ON signature demonstrating superior performance compared to existing signatures across multiple datasets.

NATURE COMMUNICATIONS (2021)

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Branched ubiquitin chain binding and deubiquitination by UCH37 facilitate proteasome clearance of stress-induced inclusions

Aixin Song et al.

Summary: UCH37, also known as UCHL5, is a highly conserved deubiquitinating enzyme that associates with the 26S proteasome and is activated by contacts with hydrophobic patches of distal Ub molecules in branched Ub chains. RPN13 further enhances branched-chain specificity by restricting linear Ub chains from accessing the UCH37 active site. In cultured human cells, UCH37 promotes substrate clearance by binding and deubiquitinating branched polyubiquitin.

ELIFE (2021)

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Article Biotechnology & Applied Microbiology

Identification and validation of an autophagy-related signature for predicting survival in lower-grade glioma

Shaobin Feng et al.

Summary: This study investigated the prognostic value of autophagy-related genes in low-grade gliomas and established a genetic signature for prognosis prediction. The signature was validated across different cohorts and associated with clinical features and pathways related to autophagy and cancer. The study provided insights for individualized survival prediction in LGG patients.

BIOENGINEERED (2021)

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Review Cell Biology

The Unfolded Protein Response as a Guardian of the Secretory Pathway

Toni Radanovic et al.

Summary: The endoplasmic reticulum (ER) is crucial for membrane biogenesis in eukaryotic cells, handling a wide range of secretory and membrane proteins. The lipid composition and stiffness of the ER membrane impact protein insertion, folding, and exit. The unfolded protein response (UPR) maintains a functional secretory pathway by regulating protein and lipid production in response to protein-folding imbalances and lipid bilayer stress.

CELLS (2021)

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Review Oncology

Optimal Therapies for Recurrent Glioblastoma: A Bayesian Network Meta-Analysis

Wenlin Chen et al.

Summary: The study compared and ranked active therapies in recurrent GBM, with BEV plus CCNU and regorafenib identified as primary recommendations for treatment due to their higher efficacy on objective response rate, 6-month progression-free survival rate, and overall survival. BEV monotherapy or combination with active drug therapies were also found to be advantageous for ORR and 6-m PFS rate. TTF plus BEV showed relatively higher SUCRA value in overall survival, indicating a potential for further investigation in future studies.

FRONTIERS IN ONCOLOGY (2021)

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Implication of BAG5 downregulation in metabolic reprogramming of cisplatin-resistant ovarian cancer cells via mTORC2 signaling pathway

Jia-Mei Wang et al.

Summary: The study found decreased expression of BAG5 in cisplatin-resistant ovarian cancer cells and tissues. BAG5 knockdown was involved in metabolic reprogramming and maintenance of cancer stem cell-like features by regulating the Rictor-mTORC2 pathway. Upregulation of Bcl6 repressed BAG5 transcription in cisplatin-resistant ovarian cancer. The study identified the Bcl6/BAG5/Rictor-mTORC2 pathway in metabolic reprogramming and maintenance of cancer stem cell-like features in cisplatin-resistant ovarian cancer cells.

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH (2021)

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Brain and other central nervous system tumor statistics, 2021

Kimberly D. Miller et al.

Summary: Brain and other CNS tumors are highly fatal cancers in the United States, with different incidence rates and survival rates among different races and age groups. Survival disparities, especially in childhood tumors, highlight the importance of providing more resources to advance research and understand the reasons behind differences in brain tumor occurrence, especially among rarer subtypes and understudied populations.

CA-A CANCER JOURNAL FOR CLINICIANS (2021)

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BAG1 down-regulation increases chemo-sensitivity of acute lymphoblastic leukaemia cells

Elena Mariotto et al.

Summary: BAG1 is deregulated in B-ALL, with levels decreasing during disease remission but drastically increasing at relapse. Depletion of BAG1 induces apoptosis and cell cycle arrest, while also increasing sensitivity to chemotherapy agents. Inhibitors of BAG1 show cytotoxic effects on B-ALL cells and synergize with pan-BCL inhibitors.

JOURNAL OF CELLULAR AND MOLECULAR MEDICINE (2021)

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The 2021 WHO Classification of Tumors of the Central Nervous System: a summary

David N. Louis et al.

Summary: The fifth edition of the WHO Classification of Tumors of the Central Nervous System integrates molecular diagnostics into CNS tumor classification, introduces different approaches to tumor nomenclature and grading, and emphasizes the importance of integrated diagnoses and layered reports.

NEURO-ONCOLOGY (2021)

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HOXA5 Is Recognized as a Prognostic-Related Biomarker and Promotes Glioma Progression Through Affecting Cell Cycle

Fengqin Ding et al.

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FRONTIERS IN ONCOLOGY (2021)

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Review Oncology

Uncovering Spatiotemporal Heterogeneity of High-Grade Gliomas: From Disease Biology to Therapeutic Implications

Andrea Comba et al.

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FRONTIERS IN ONCOLOGY (2021)

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Bcl-2 Associated Athanogene 2 (BAG2) is Associated With Progression and Prognosis of Hepatocellular Carcinoma: A Bioinformatics-Based Analysis

Xi Zhang et al.

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Transglutaminase type 2-dependent selective recruitment of proteins into exosomes under stressful cellular conditions

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BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH (2016)

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BAG2 structure, function and involvement in disease

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CELLULAR & MOLECULAR BIOLOGY LETTERS (2016)

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GRP78 Interacting Partner Bag5 Responds to ER Stress and Protects Cardiomyocytes From ER Stress-Induced Apoptosis

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JOURNAL OF CELLULAR BIOCHEMISTRY (2016)

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Review Oncology

Targeting autophagy to sensitive glioma to temozolomide treatment

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JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH (2016)

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MicroRNA-127-3p acts as a tumor suppressor in epithelial ovarian cancer by regulating the BAG5 gene

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ONCOLOGY REPORTS (2016)

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Bafilomycin A1 induces caspase-independent cell death in hepatocellular carcinoma cells via targeting of autophagy and MAPK pathways

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SCIENTIFIC REPORTS (2016)

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Annexin A7 modulates BAG4 and BAG4-binding proteins in mitochondrial apoptosis

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BIOMEDICINE & PHARMACOTHERAPY (2015)

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Article Biochemistry & Molecular Biology

Lysosomal mTORC2/PHLPP1/Akt Regulate Chaperone-Mediated Autophagy

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MOLECULAR CELL (2015)

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Review Cell Biology

Extracellular Vesicles in Cancer: Exosomes, Microvesicles and the Emerging Role of Large Oncosomes

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SEMINARS IN CELL & DEVELOPMENTAL BIOLOGY (2015)

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BAG2 promotes tumorigenesis through enhancing mutant p53 protein levels and function

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BAG3 protects against hyperthermic stress by modulating NF-κB and ERK activities in human retinoblastoma cells

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WW Domain of BAG3 Is Required for the Induction of Autophagy in Glioma Cells

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JOURNAL OF CELLULAR PHYSIOLOGY (2015)

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Proteomic Analysis Reveals a Role for Bcl2-associated Athanogene 3 and Major Vault Protein in Resistance to Apoptosis in Senescent Cells by Regulating ERK1/2 Activation

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Spautin-1, a novel autophagy inhibitor, enhances imatinib-induced apoptosis in chronic myeloid leukemia

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INTERNATIONAL JOURNAL OF ONCOLOGY (2014)

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Bafilomycin A1 inhibits autophagy and induces apoptosis in MG63 osteosarcoma cells

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MOLECULAR MEDICINE REPORTS (2014)

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Roles of Heat Shock Factor 1 in Neuronal Response to Fetal Environmental Risks and Its Relevance to Brain Disorders

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BAG3 induction is required to mitigate proteotoxicity via selective autophagy following inhibition of constitutive protein degradation pathways

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ONCOGENE (2014)

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The impact of the endoplasmic reticulum protein-folding environment on cancer development

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Bag6/Bat3/Scythe: A novel chaperone activity with diverse regulatory functions in protein biogenesis and degradation

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Bcl-2 associated athanogene 5 (Bag5) is overexpressed in prostate cancer and inhibits ER-stress induced apoptosis

Anja Bruchmann et al.

BMC CANCER (2013)

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Review Biochemistry & Molecular Biology

BAG6/BAT3: emerging roles in quality control for nascent polypeptides

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JOURNAL OF BIOCHEMISTRY (2013)

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Microenvironmental regulation of tumor progression and metastasis

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Allosteric opening of the polypeptide-binding site when an Hsp70 binds ATP

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NATURE STRUCTURAL & MOLECULAR BIOLOGY (2013)

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Exosomes reflect the hypoxic status of glioma cells and mediate hypoxia-dependent activation of vascular cells during tumor development

Paulina Kucharzewska et al.

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA (2013)

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Structure and Dynamics of the ATP-Bound Open Conformation of Hsp70 Chaperones

Roman Kityk et al.

MOLECULAR CELL (2012)

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The Transcription Factor TFEB Links mTORC1 Signaling to Transcriptional Control of Lysosome Homeostasis

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Transcriptional Activation of Lysosomal Exocytosis Promotes Cellular Clearance

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DEVELOPMENTAL CELL (2011)

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BAG3 mediates chaperone-based aggresome-targeting and selective autophagy of misfolded proteins

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EMBO REPORTS (2011)

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Role of Chaperone Mediated Autophagy (CMA) in the Degradation of Misfolded N-CoR Protein in Non-Small Cell Lung Cancer (NSCLC) Cells

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PLOS ONE (2011)

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BAG1: The Guardian of Anti-Apoptotic Proteins in Acute Myeloid Leukemia

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PLOS ONE (2011)

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BAG3: a multifaceted protein that regulates major cell pathways

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CELL DEATH & DISEASE (2011)

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ER stress negatively regulates AKT/TSC/mTOR pathway to enhance autophagy

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AUTOPHAGY (2010)

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ATP-Dependent Steps in the Binding of Ubiquitin Conjugates to the 26S Proteasome that Commit to Degradation

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MOLECULAR CELL (2010)

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Enhancement of proteasome activity by a small-molecule inhibitor of USP14

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Role of Hsp70 ATPase Domain Intrinsic Dynamics and Sequence Evolution in Enabling its Functional Interactions with NEFs

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PLOS COMPUTATIONAL BIOLOGY (2010)

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Extent of MGMT promoter methylation correlates with outcome in glioblastomas given temozolomide and radiotherapy

J. Dunn et al.

BRITISH JOURNAL OF CANCER (2009)

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BAG3 gene silencing sensitizes leukemic cells to Bortezomib-induced apoptosis

Peng Liu et al.

FEBS LETTERS (2009)

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Ubiquitin-like protein activation by E1 enzymes: the apex for downstream signalling pathways

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IDH1 and IDH2 Mutations in Gliomas

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NEW ENGLAND JOURNAL OF MEDICINE (2009)

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hsp70 genes in the human genome:: Conservation and differentiation patterns predict a wide array of overlapping and specialized functions

Luciano Brocchieri et al.

BMC EVOLUTIONARY BIOLOGY (2008)

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bag3 gene expression is regulated by heat shock factor 1

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JOURNAL OF CELLULAR PHYSIOLOGY (2008)

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Comprehensive genomic characterization defines human glioblastoma genes and core pathways

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Intercellular transfer of the oncogenic receptor EGFrvIII by microvesicles derived from tumour cells

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Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers

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NATURE CELL BIOLOGY (2008)

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Structural basis of nucleotide exchange and client binding by the Hsp70 cochaperone Bag2

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NATURE STRUCTURAL & MOLECULAR BIOLOGY (2008)

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Article Biochemistry & Molecular Biology

Docking of the proteasomal ATPases' carboxyl termini in the 20S proteasome's α ring opens the gate for substrate entry

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The role of epithelial-mesenchymal transition in cancer pathology

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Adaptation to ER stress is mediated by differential stabilities of pro-survival and pro-apoptotic mRNAs and proteins

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The regulation of exosome secretion: a novel function of the p53 protein

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CANCER RESEARCH (2006)

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Adding chloroquine to conventional treatment for glioblastoma multiforme -: A randomized, double-blind, placebo-controlled trial

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ANNALS OF INTERNAL MEDICINE (2006)

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Article Medicine, General & Internal

MGMT gene silencing and benefit from temozolomide in glioblastoma

ME Hegi et al.

NEW ENGLAND JOURNAL OF MEDICINE (2005)

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BAG5 inhibits parkin and enhances dopaminergic neuron degeneration

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NEURON (2004)

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Identification of SNAREs involved in synaptotagmin VII-regulated lysosomal exocytosis

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Role of Rpn11 metalloprotease in deubiquitination and degradation by the 26S proteasome

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SCIENCE (2002)

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BAG4/SODD protein contains a short BAG domain

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JOURNAL OF BIOLOGICAL CHEMISTRY (2002)

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The co-chaperone CHIP regulates protein triage decisions mediated by heat-shock proteins

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NATURE CELL BIOLOGY (2001)

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The ubiquitin-related BAG-1 provides a link between the molecular chaperones Hsc70/Hsp70 and the proteasome

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