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  1. Article ; Online: Differential optineurin expression controls TGFβ signaling and is a key determinant for metastasis of triple negative breast cancer.

    Liu, Sijia / van Dinther, Maarten / Hagenaars, Sophie C / Gu, Yuanzhuo / Kuipers, Thomas B / Mei, Hailiang / Gomez-Puerto, Maria Catalina / Mesker, Wilma E / Ten Dijke, Peter

    International journal of cancer

    2023  Volume 152, Issue 12, Page(s) 2594–2606

    Abstract: Triple-negative breast cancer (TNBC) is the most challenging breast cancer subtype to treat due to its aggressive characteristics and low response to the existing clinical therapies. Distant metastasis is the main cause of death of TNBC patients. Better ... ...

    Abstract Triple-negative breast cancer (TNBC) is the most challenging breast cancer subtype to treat due to its aggressive characteristics and low response to the existing clinical therapies. Distant metastasis is the main cause of death of TNBC patients. Better understanding of the mechanisms underlying TNBC metastasis may lead to new strategies of early diagnosis and more efficient treatment. In our study, we uncovered that the autophagy receptor optineurin (OPTN) plays an unexpected role in TNBC metastasis. Data mining of publicly available data bases revealed that the mRNA level of OPTN in TNBC patients positively correlates with relapse free and distance metastasis free survival. Importantly, in vitro and in vivo models demonstrated that OPTN suppresses TNBC metastasis. Mechanistically, OPTN inhibited the pro-oncogenic transforming growth factor-β (TGFβ) signaling in TNBC cells by interacting with TGFβ type I receptor (TβRI) and promoting its ubiquitination for degradation. Consistent with our experimental findings, the clinical TNBC samples displayed a negative correlation between OPTN mRNA expression and TGFβ gene response signature and expression of proto-typic TGFβ target genes. Altogether, our study demonstrates that OPTN is a negative regulator for TGFβ receptor/SMAD signaling and suppresses metastasis in TNBC.
    MeSH term(s) Humans ; Cell Line, Tumor ; Neoplasm Metastasis ; Neoplasm Recurrence, Local ; RNA, Messenger/genetics ; Transforming Growth Factor beta/genetics ; Transforming Growth Factor beta/metabolism ; Triple Negative Breast Neoplasms/pathology ; Cell Cycle Proteins/metabolism ; Membrane Transport Proteins/metabolism
    Chemical Substances RNA, Messenger ; Transforming Growth Factor beta ; OPTN protein, human ; Cell Cycle Proteins ; Membrane Transport Proteins
    Language English
    Publishing date 2023-03-08
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 218257-9
    ISSN 1097-0215 ; 0020-7136
    ISSN (online) 1097-0215
    ISSN 0020-7136
    DOI 10.1002/ijc.34483
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    Zs.A 478: Show issues Location:
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  2. Article ; Online: BMP type II receptor as a therapeutic target in pulmonary arterial hypertension.

    Orriols, Mar / Gomez-Puerto, Maria Catalina / Ten Dijke, Peter

    Cellular and molecular life sciences : CMLS

    2017  Volume 74, Issue 16, Page(s) 2979–2995

    Abstract: Pulmonary arterial hypertension (PAH) is a chronic disease characterized by a progressive elevation in mean pulmonary arterial pressure. This occurs due to abnormal remodeling of small peripheral lung vasculature resulting in progressive occlusion of the ...

    Abstract Pulmonary arterial hypertension (PAH) is a chronic disease characterized by a progressive elevation in mean pulmonary arterial pressure. This occurs due to abnormal remodeling of small peripheral lung vasculature resulting in progressive occlusion of the artery lumen that eventually causes right heart failure and death. The most common cause of PAH is inactivating mutations in the gene encoding a bone morphogenetic protein type II receptor (BMPRII). Current therapeutic options for PAH are limited and focused mainly on reversal of pulmonary vasoconstriction and proliferation of vascular cells. Although these treatments can relieve disease symptoms, PAH remains a progressive lethal disease. Emerging data suggest that restoration of BMPRII signaling in PAH is a promising alternative that could prevent and reverse pulmonary vascular remodeling. Here we will focus on recent advances in rescuing BMPRII expression, function or signaling to prevent and reverse pulmonary vascular remodeling in PAH and its feasibility for clinical translation. Furthermore, we summarize the role of described miRNAs that directly target the BMPR2 gene in blood vessels. We discuss the therapeutic potential and the limitations of promising new approaches to restore BMPRII signaling in PAH patients. Different mutations in BMPR2 and environmental/genetic factors make PAH a heterogeneous disease and it is thus likely that the best approach will be patient-tailored therapies.
    MeSH term(s) Animals ; Bone Morphogenetic Protein Receptors, Type II/analysis ; Bone Morphogenetic Protein Receptors, Type II/genetics ; Bone Morphogenetic Protein Receptors, Type II/metabolism ; Disease Models, Animal ; Endothelial Cells/drug effects ; Endothelial Cells/metabolism ; Endothelial Cells/pathology ; Gene Expression Regulation ; Gene Transfer Techniques ; Genetic Therapy ; Humans ; Hypertension, Pulmonary/genetics ; Hypertension, Pulmonary/metabolism ; Hypertension, Pulmonary/pathology ; Hypertension, Pulmonary/therapy ; MicroRNAs/analysis ; MicroRNAs/genetics ; MicroRNAs/metabolism ; Molecular Targeted Therapy ; Muscle, Smooth, Vascular/cytology ; Muscle, Smooth, Vascular/drug effects ; Muscle, Smooth, Vascular/metabolism ; Muscle, Smooth, Vascular/pathology ; Pulmonary Artery/drug effects ; Pulmonary Artery/metabolism ; Pulmonary Artery/pathology ; Signal Transduction/drug effects ; Smad Proteins/metabolism
    Chemical Substances MicroRNAs ; Smad Proteins ; BMPR2 protein, human (EC 2.7.11.30) ; Bone Morphogenetic Protein Receptors, Type II (EC 2.7.11.30)
    Language English
    Publishing date 2017-08
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 1358415-7
    ISSN 1420-9071 ; 1420-682X
    ISSN (online) 1420-9071
    ISSN 1420-682X
    DOI 10.1007/s00018-017-2510-4
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  3. Article ; Online: Erratum to: BMP type II receptor as a therapeutic target in pulmonary arterial hypertension.

    Orriols, Mar / Gomez-Puerto, Maria Catalina / Ten Dijke, Peter

    Cellular and molecular life sciences : CMLS

    2017  Volume 74, Issue 16, Page(s) 2997

    Language English
    Publishing date 2017-05-18
    Publishing country Switzerland
    Document type Journal Article ; Published Erratum
    ZDB-ID 1358415-7
    ISSN 1420-9071 ; 1420-682X
    ISSN (online) 1420-9071
    ISSN 1420-682X
    DOI 10.1007/s00018-017-2543-8
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  4. Article ; Online: The polarity protein Par3 coordinates positively self-renewal and negatively invasiveness in glioblastoma.

    Dadras, Mahsa Shahidi / Caja, Laia / Mezheyeuski, Artur / Liu, Sijia / Gélabert, Caroline / Gomez-Puerto, Maria Catalina / Gallini, Radiosa / Rubin, Carl-Johan / Ten Dijke, Peter / Heldin, Carl-Henrik / Moustakas, Aristidis

    Cell death & disease

    2021  Volume 12, Issue 10, Page(s) 932

    Abstract: Glioblastoma (GBM) is a brain malignancy characterized by invasiveness to the surrounding brain tissue and by stem-like cells, which propagate the tumor and may also regulate invasiveness. During brain development, polarity proteins, such as Par3, ... ...

    Abstract Glioblastoma (GBM) is a brain malignancy characterized by invasiveness to the surrounding brain tissue and by stem-like cells, which propagate the tumor and may also regulate invasiveness. During brain development, polarity proteins, such as Par3, regulate asymmetric cell division of neuro-glial progenitors and neurite motility. We, therefore, studied the role of the Par3 protein (encoded by PARD3) in GBM. GBM patient transcriptomic data and patient-derived culture analysis indicated diverse levels of expression of PARD3 across and independent from subtypes. Multiplex immunolocalization in GBM tumors identified Par3 protein enrichment in SOX2-, CD133-, and NESTIN-positive (stem-like) cells. Analysis of GBM cultures of the three subtypes (proneural, classical, mesenchymal), revealed decreased gliomasphere forming capacity and enhanced invasiveness upon silencing Par3. GBM cultures with suppressed Par3 showed low expression of stemness (SOX2 and NESTIN) but higher expression of differentiation (GFAP) genes. Moreover, Par3 silencing reduced the expression of a set of genes encoding mitochondrial enzymes that generate ATP. Accordingly, silencing Par3 reduced ATP production and concomitantly increased reactive oxygen species. The latter was required for the enhanced migration observed upon silencing of Par3 as anti-oxidants blocked the enhanced migration. These findings support the notion that Par3 exerts homeostatic redox control, which could limit the tumor cell-derived pool of oxygen radicals, and thereby the tumorigenicity of GBM.
    MeSH term(s) Adaptor Proteins, Signal Transducing/genetics ; Adaptor Proteins, Signal Transducing/metabolism ; Adenosine Triphosphate/metabolism ; Animals ; Antioxidants/metabolism ; Cell Cycle Proteins/genetics ; Cell Cycle Proteins/metabolism ; Cell Line, Tumor ; Cell Movement ; Cell Polarity/genetics ; Cell Self Renewal ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic ; Gene Silencing ; Glioblastoma/genetics ; Glioblastoma/pathology ; Humans ; Mitochondria/metabolism ; Neoplasm Invasiveness ; Oxidative Phosphorylation ; Reactive Oxygen Species/metabolism ; Spheroids, Cellular/metabolism ; Spheroids, Cellular/pathology ; Transcriptome/genetics ; Zebrafish
    Chemical Substances Adaptor Proteins, Signal Transducing ; Antioxidants ; Cell Cycle Proteins ; PARD3 protein, human ; Reactive Oxygen Species ; Adenosine Triphosphate (8L70Q75FXE)
    Language English
    Publishing date 2021-10-12
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2541626-1
    ISSN 2041-4889 ; 2041-4889
    ISSN (online) 2041-4889
    ISSN 2041-4889
    DOI 10.1038/s41419-021-04220-7
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: TGF-β-Induced Endothelial-Mesenchymal Transition in Fibrotic Diseases.

    Pardali, Evangelia / Sanchez-Duffhues, Gonzalo / Gomez-Puerto, Maria Catalina / Ten Dijke, Peter

    International journal of molecular sciences

    2017  Volume 18, Issue 10

    Abstract: Fibrotic diseases are characterized by net accumulation of extracellular matrix proteins in affected organs leading to their dysfunction and ultimate failure. Myofibroblasts have been identified as the cells responsible for the progression of the ... ...

    Abstract Fibrotic diseases are characterized by net accumulation of extracellular matrix proteins in affected organs leading to their dysfunction and ultimate failure. Myofibroblasts have been identified as the cells responsible for the progression of the fibrotic process, and they originate from several sources, including quiescent tissue fibroblasts, circulating CD34⁺ fibrocytes and the phenotypic conversion of various cell types into activated myofibroblasts. Several studies have demonstrated that endothelial cells can transdifferentiate into mesenchymal cells through a process termed endothelial- mesenchymal transition (EndMT) and that this can give rise to activated myofibroblasts involved in the development of fibrotic diseases. Transforming growth factor β (TGF-β) has a central role in fibrogenesis by modulating the fibroblast phenotype and function, inducing myofibroblast transdifferentiation and promoting matrix accumulation. In addition, TGF-β by inducing EndMT may further contribute to the development of fibrosis. Despite extensive investigation of the pathogenesis of fibrotic diseases, no effective treatment strategies are available. Delineation of the mechanisms responsible for initiation and progression of fibrotic diseases is crucial for the development of therapeutic strategies for the treatment of the disease. In this review, we summarize the role of the TGF-β signaling pathway and EndMT in the development of fibrotic diseases and discuss their therapeutic potential.
    Language English
    Publishing date 2017-10-17
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2019364-6
    ISSN 1422-0067 ; 1422-0067 ; 1661-6596
    ISSN (online) 1422-0067
    ISSN 1422-0067 ; 1661-6596
    DOI 10.3390/ijms18102157
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  6. Article ; Online: The protein kinase LKB1 promotes self-renewal and blocks invasiveness in glioblastoma.

    Caja, Laia / Dadras, Mahsa Shahidi / Mezheyeuski, Artur / Rodrigues-Junior, Dorival Mendes / Liu, Sijia / Webb, Anna Taylor / Gomez-Puerto, Maria Catalina / Ten Dijke, Peter / Heldin, Carl-Henrik / Moustakas, Aristidis

    Journal of cellular physiology

    2021  Volume 237, Issue 1, Page(s) 743–762

    Abstract: The role of liver kinase B1 (LKB1) in glioblastoma (GBM) development remains poorly understood. LKB1 may regulate GBM cell metabolism and has been suggested to promote glioma invasiveness. After analyzing LKB1 expression in GBM patient mRNA databases and ...

    Abstract The role of liver kinase B1 (LKB1) in glioblastoma (GBM) development remains poorly understood. LKB1 may regulate GBM cell metabolism and has been suggested to promote glioma invasiveness. After analyzing LKB1 expression in GBM patient mRNA databases and in tumor tissue via multiparametric immunohistochemistry, we observed that LKB1 was localized and enriched in GBM tumor cells that co-expressed SOX2 and NESTIN stemness markers. Thus, LKB1-specific immunohistochemistry can potentially reveal subpopulations of stem-like cells, advancing GBM patient molecular pathology. We further analyzed the functions of LKB1 in patient-derived GBM cultures under defined serum-free conditions. Silencing of endogenous LKB1 impaired 3D-gliomasphere frequency and promoted GBM cell invasion in vitro and in the zebrafish collagenous tail after extravasation of circulating GBM cells. Moreover, loss of LKB1 function revealed mitochondrial dysfunction resulting in decreased ATP levels. Treatment with the clinically used drug metformin impaired 3D-gliomasphere formation and enhanced cytotoxicity induced by temozolomide, the primary chemotherapeutic drug against GBM. The IC
    MeSH term(s) AMP-Activated Protein Kinase Kinases/metabolism ; Animals ; Brain Neoplasms/drug therapy ; Brain Neoplasms/genetics ; Brain Neoplasms/pathology ; Cell Line, Tumor ; Cell Proliferation/genetics ; Gene Expression Regulation, Neoplastic ; Glioblastoma/drug therapy ; Glioblastoma/genetics ; Glioblastoma/metabolism ; Humans ; Metformin/pharmacology ; Neoplastic Stem Cells/pathology ; Protein Kinases/genetics ; Temozolomide/pharmacology ; Zebrafish/metabolism
    Chemical Substances Metformin (9100L32L2N) ; Protein Kinases (EC 2.7.-) ; STK11 protein, human (EC 2.7.11.1) ; AMP-Activated Protein Kinase Kinases (EC 2.7.11.3) ; Temozolomide (YF1K15M17Y)
    Language English
    Publishing date 2021-08-05
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 3116-1
    ISSN 1097-4652 ; 0021-9541
    ISSN (online) 1097-4652
    ISSN 0021-9541
    DOI 10.1002/jcp.30542
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  7. Article ; Online: Bone morphogenetic protein receptor signal transduction in human disease.

    Gomez-Puerto, Maria Catalina / Iyengar, Prasanna Vasudevan / García de Vinuesa, Amaya / Ten Dijke, Peter / Sanchez-Duffhues, Gonzalo

    The Journal of pathology

    2018  Volume 247, Issue 1, Page(s) 9–20

    Abstract: Bone morphogenetic proteins (BMPs) are secreted cytokines that were initially discovered on the basis of their ability to induce bone. Several decades of research have now established that these proteins function in a large variety of physiopathological ... ...

    Abstract Bone morphogenetic proteins (BMPs) are secreted cytokines that were initially discovered on the basis of their ability to induce bone. Several decades of research have now established that these proteins function in a large variety of physiopathological processes. There are about 15 BMP family members, which signal via three transmembrane type II receptors and four transmembrane type I receptors. Mechanistically, BMP binding leads to phosphorylation of the type I receptor by the type II receptor. This activated heteromeric complex triggers intracellular signaling that is initiated by phosphorylation of receptor-regulated SMAD1, 5, and 8 (also termed R-SMADs). Activated R-SMADs form heteromeric complexes with SMAD4, which engage in specific transcriptional responses. There is convergence along the signaling pathway and, besides the canonical SMAD pathway, BMP-receptor activation can also induce non-SMAD signaling. Each step in the pathway is fine-tuned by positive and negative regulation and crosstalk with other signaling pathways. For example, ligand bioavailability for the receptor can be regulated by ligand-binding proteins that sequester the ligand from interacting with receptors. Accessory co-receptors, also known as BMP type III receptors, lack intrinsic enzymatic activity but enhance BMP signaling by presenting ligands to receptors. In this review, we discuss the role of BMP receptor signaling and how corruption of this pathway contributes to cardiovascular and musculoskeletal diseases and cancer. We describe pharmacological tools to interrogate the function of BMP receptor signaling in specific biological processes and focus on how these agents can be used as drugs to inhibit or activate the function of the receptor, thereby normalizing dysregulated BMP signaling. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
    MeSH term(s) Animals ; Bone Morphogenetic Protein Receptors/genetics ; Bone Morphogenetic Protein Receptors/metabolism ; Bone Morphogenetic Proteins/genetics ; Bone Morphogenetic Proteins/metabolism ; Cardiovascular Diseases/genetics ; Cardiovascular Diseases/metabolism ; Cardiovascular Diseases/pathology ; Cardiovascular Diseases/physiopathology ; Humans ; Ligands ; Musculoskeletal Diseases/genetics ; Musculoskeletal Diseases/metabolism ; Musculoskeletal Diseases/pathology ; Musculoskeletal Diseases/physiopathology ; Neoplasms/genetics ; Neoplasms/metabolism ; Neoplasms/pathology ; Neoplasms/physiopathology ; Phosphorylation ; Signal Transduction ; Smad Proteins, Receptor-Regulated/metabolism
    Chemical Substances Bone Morphogenetic Proteins ; Ligands ; Smad Proteins, Receptor-Regulated ; Bone Morphogenetic Protein Receptors (EC 2.7.11.30)
    Language English
    Publishing date 2018-11-27
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 3119-7
    ISSN 1096-9896 ; 0022-3417
    ISSN (online) 1096-9896
    ISSN 0022-3417
    DOI 10.1002/path.5170
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    Ud II Zs.12: Show issues Location:
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  8. Article ; Online: MnTBAP Reverses Pulmonary Vascular Remodeling and Improves Cardiac Function in Experimentally Induced Pulmonary Arterial Hypertension.

    Gomez-Puerto, Maria Catalina / Sun, Xiao-Qing / Schalij, Ingrid / Orriols, Mar / Pan, Xiaoke / Szulcek, Robert / Goumans, Marie-José / Bogaard, Harm-Jan / Zhou, Qian / Ten Dijke, Peter

    International journal of molecular sciences

    2020  Volume 21, Issue 11

    Abstract: Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by obstructed pulmonary vasculatures. Current therapies for PAH are limited and only alleviate symptoms. Reduced levels of BMPR2 are associated with PAH pathophysiology. ... ...

    Abstract Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by obstructed pulmonary vasculatures. Current therapies for PAH are limited and only alleviate symptoms. Reduced levels of BMPR2 are associated with PAH pathophysiology. Moreover, reactive oxygen species, inflammation and autophagy have been shown to be hallmarks in PAH. We previously demonstrated that MnTBAP, a synthetic metalloporphyrin with antioxidant and anti-inflammatory activity, inhibits the turn-over of BMPR2 in human umbilical vein endothelial cells. Therefore, we hypothesized that MnTBAP might be used to treat PAH. Human pulmonary artery endothelial cells (PAECs), as well as pulmonary microvascular endothelial (MVECs) and smooth muscle cells (MVSMCs) from PAH patients, were treated with MnTBAP. In vivo, either saline or MnTBAP was given to PAH rats induced by Sugen 5416 and hypoxia (SuHx). On PAECs, MnTBAP was found to increase BMPR2 protein levels by blocking autophagy. Moreover, MnTBAP increased BMPR2 levels in pulmonary MVECs and MVSMCs isolated from PAH patients. In SuHx rats, MnTBAP reduced right ventricular (RV) afterload by reversing pulmonary vascular remodeling, including both intima and media layers. Furthermore, MnTBAP improved RV function and reversed RV dilation in SuHx rats. Taken together, these data highlight the importance of MnTBAP as a potential therapeutic treatment for PAH.
    MeSH term(s) Animals ; Autophagy/drug effects ; Bone Morphogenetic Protein Receptors, Type II/genetics ; Bone Morphogenetic Protein Receptors, Type II/metabolism ; Cells, Cultured ; Disease Models, Animal ; Endothelial Cells/drug effects ; Endothelial Cells/metabolism ; Heart Function Tests ; Humans ; Male ; Metalloporphyrins/pharmacology ; Muscle, Smooth, Vascular/cytology ; Muscle, Smooth, Vascular/pathology ; Pulmonary Arterial Hypertension/chemically induced ; Pulmonary Arterial Hypertension/drug therapy ; Pulmonary Arterial Hypertension/physiopathology ; Pulmonary Artery/cytology ; Pulmonary Artery/drug effects ; Pulmonary Artery/pathology ; Rats, Sprague-Dawley ; Vascular Remodeling/drug effects
    Chemical Substances Metalloporphyrins ; manganese(III)-tetrakis(4-benzoic acid)porphyrin ; BMPR2 protein, human (EC 2.7.11.30) ; Bone Morphogenetic Protein Receptors, Type II (EC 2.7.11.30)
    Language English
    Publishing date 2020-06-10
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2019364-6
    ISSN 1422-0067 ; 1422-0067 ; 1661-6596
    ISSN (online) 1422-0067
    ISSN 1422-0067 ; 1661-6596
    DOI 10.3390/ijms21114130
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  9. Article ; Online: Autophagy Proteins ATG5 and ATG7 Are Essential for the Maintenance of Human CD34(+) Hematopoietic Stem-Progenitor Cells.

    Gomez-Puerto, Maria Catalina / Folkerts, Hendrik / Wierenga, Albertus T J / Schepers, Koen / Schuringa, Jan Jacob / Coffer, Paul J / Vellenga, Edo

    Stem cells (Dayton, Ohio)

    2016  Volume 34, Issue 6, Page(s) 1651–1663

    Abstract: Autophagy is a highly regulated catabolic process that involves sequestration and lysosomal degradation of cytosolic components such as damaged organelles and misfolded proteins. While autophagy can be considered to be a general cellular housekeeping ... ...

    Abstract Autophagy is a highly regulated catabolic process that involves sequestration and lysosomal degradation of cytosolic components such as damaged organelles and misfolded proteins. While autophagy can be considered to be a general cellular housekeeping process, it has become clear that it may also play cell type-dependent functional roles. In this study, we analyzed the functional importance of autophagy in human hematopoietic stem/progenitor cells (HSPCs), and how this is regulated during differentiation. Western blot-based analysis of LC3-II and p62 levels, as well as flow cytometry-based autophagic vesicle quantification, demonstrated that umbilical cord blood-derived CD34(+) /CD38(-) immature hematopoietic progenitors show a higher autophagic flux than CD34(+) /CD38(+) progenitors and more differentiated myeloid and erythroid cells. This high autophagic flux was critical for maintaining stem and progenitor function since knockdown of autophagy genes ATG5 or ATG7 resulted in reduced HSPC frequencies in vitro as well as in vivo. The reduction in HSPCs was not due to impaired differentiation, but at least in part due to reduced cell cycle progression and increased apoptosis. This is accompanied by increased expression of p53, proapoptotic genes BAX and PUMA, and the cell cycle inhibitor p21, as well as increased levels of cleaved caspase-3 and reactive oxygen species. Taken together, our data demonstrate that autophagy is an important regulatory mechanism for human HSCs and their progeny, reducing cellular stress and promoting survival. Stem Cells 2016;34:1651-1663.
    Language English
    Publishing date 2016-06
    Publishing country United States
    Document type Journal Article
    ZDB-ID 1143556-2
    ISSN 1549-4918 ; 1066-5099
    ISSN (online) 1549-4918
    ISSN 1066-5099
    DOI 10.1002/stem.2347
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  10. Article ; Online: Autophagy contributes to BMP type 2 receptor degradation and development of pulmonary arterial hypertension.

    Gomez-Puerto, Maria Catalina / van Zuijen, Iris / Huang, Christopher Jz / Szulcek, Robert / Pan, Xiaoke / van Dinther, Maarten Ah / Kurakula, Kondababu / Wiesmeijer, Catharina C / Goumans, Marie-Jose / Bogaard, Harm-Jan / Morrell, Nicholas W / Rana, Amer Ahmed / Ten Dijke, Peter

    The Journal of pathology

    2019  Volume 249, Issue 3, Page(s) 356–367

    Abstract: Pulmonary arterial hypertension (PAH) is characterised by an increase in mean pulmonary arterial pressure which almost invariably leads to right heart failure and premature death. More than 70% of familial PAH and 20% of idiopathic PAH patients carry ... ...

    Abstract Pulmonary arterial hypertension (PAH) is characterised by an increase in mean pulmonary arterial pressure which almost invariably leads to right heart failure and premature death. More than 70% of familial PAH and 20% of idiopathic PAH patients carry heterozygous mutations in the bone morphogenetic protein (BMP) type 2 receptor (BMPR2). However, the incomplete penetrance of BMPR2 mutations suggests that other genetic and environmental factors contribute to the disease. In the current study, we investigate the contribution of autophagy in the degradation of BMPR2 in pulmonary vascular cells. We demonstrate that endogenous BMPR2 is degraded through the lysosome in primary human pulmonary artery endothelial (PAECs) and smooth muscle cells (PASMCs): two cell types that play a key role in the pathology of the disease. By means of an elegant HaloTag system, we show that a block in lysosomal degradation leads to increased levels of BMPR2 at the plasma membrane. In addition, pharmacological or genetic manipulations of autophagy allow us to conclude that autophagy activation contributes to BMPR2 degradation. It has to be further investigated whether the role of autophagy in the degradation of BMPR2 is direct or through the modulation of the endocytic pathway. Interestingly, using an iPSC-derived endothelial cell model, our findings indicate that BMPR2 heterozygosity alone is sufficient to cause an increased autophagic flux. Besides BMPR2 heterozygosity, pro-inflammatory cytokines also contribute to an augmented autophagy in lung vascular cells. Furthermore, we demonstrate an increase in microtubule-associated protein 1 light chain 3 beta (MAP1LC3B) levels in lung sections from PAH induced in rats. Accordingly, pulmonary microvascular endothelial cells (MVECs) from end-stage idiopathic PAH patients present an elevated autophagic flux. Our findings support a model in which an increased autophagic flux in PAH patients contributes to a greater decrease in BMPR2 levels. Altogether, this study sheds light on the basic mechanisms of BMPR2 degradation and highlights a crucial role for autophagy in PAH. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
    MeSH term(s) Adult ; Aged ; Aged, 80 and over ; Animals ; Arterial Pressure ; Autophagy ; Bone Morphogenetic Protein Receptors, Type II/genetics ; Bone Morphogenetic Protein Receptors, Type II/metabolism ; Cell Line ; Cytokines/metabolism ; Disease Models, Animal ; Endothelial Cells/metabolism ; Endothelial Cells/pathology ; Female ; Heterozygote ; Humans ; Inflammation Mediators/metabolism ; Lysosomes/metabolism ; Lysosomes/pathology ; Male ; Microtubule-Associated Proteins/metabolism ; Middle Aged ; Muscle, Smooth, Vascular/metabolism ; Muscle, Smooth, Vascular/pathology ; Muscle, Smooth, Vascular/physiopathology ; Myocytes, Smooth Muscle/metabolism ; Myocytes, Smooth Muscle/pathology ; Proteolysis ; Pulmonary Arterial Hypertension/metabolism ; Pulmonary Arterial Hypertension/pathology ; Pulmonary Arterial Hypertension/physiopathology ; Pulmonary Artery/metabolism ; Pulmonary Artery/pathology ; Pulmonary Artery/physiopathology ; Rats ; Signal Transduction ; Young Adult
    Chemical Substances Cytokines ; Inflammation Mediators ; Microtubule-Associated Proteins ; BMPR2 protein, human (EC 2.7.11.30) ; Bmpr2 protein, rat (EC 2.7.11.30) ; Bone Morphogenetic Protein Receptors, Type II (EC 2.7.11.30)
    Language English
    Publishing date 2019-08-27
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 3119-7
    ISSN 1096-9896 ; 0022-3417
    ISSN (online) 1096-9896
    ISSN 0022-3417
    DOI 10.1002/path.5322
    Database MEDical Literature Analysis and Retrieval System OnLINE

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