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  1. Article: Editorial: Targeting Cardiac Proteotoxicity.

    Ranek, Mark J / Bhuiyan, Md Shenuarin / Wang, Xuejun

    Frontiers in physiology

    2021  Volume 12, Page(s) 669356

    Language English
    Publishing date 2021-03-25
    Publishing country Switzerland
    Document type Editorial
    ZDB-ID 2564217-0
    ISSN 1664-042X
    ISSN 1664-042X
    DOI 10.3389/fphys.2021.669356
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: Editorial: Post-translational Modifications and Compartmentalized Protein Quality Control in Cardiac Muscle and Disease.

    Ranek, Mark J / Gomes, Aldrin V / Su, Huabo

    Frontiers in physiology

    2021  Volume 12, Page(s) 745887

    Language English
    Publishing date 2021-08-30
    Publishing country Switzerland
    Document type Editorial
    ZDB-ID 2564217-0
    ISSN 1664-042X
    ISSN 1664-042X
    DOI 10.3389/fphys.2021.745887
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article: Phosphorylation Modifications Regulating Cardiac Protein Quality Control Mechanisms.

    Mishra, Sumita / Dunkerly-Eyring, Brittany L / Keceli, Gizem / Ranek, Mark J

    Frontiers in physiology

    2020  Volume 11, Page(s) 593585

    Abstract: Many forms of cardiac disease, including heart failure, present with inadequate protein quality control (PQC). Pathological conditions often involve impaired removal of terminally misfolded proteins. This results in the formation of large protein ... ...

    Abstract Many forms of cardiac disease, including heart failure, present with inadequate protein quality control (PQC). Pathological conditions often involve impaired removal of terminally misfolded proteins. This results in the formation of large protein aggregates, which further reduce cellular viability and cardiac function. Cardiomyocytes have an intricately collaborative PQC system to minimize cellular proteotoxicity. Increased expression of chaperones or enhanced clearance of misfolded proteins either by the proteasome or lysosome has been demonstrated to attenuate disease pathogenesis, whereas reduced PQC exacerbates pathogenesis. Recent studies have revealed that phosphorylation of key proteins has a potent regulatory role, both promoting and hindering the PQC machinery. This review highlights the recent advances in phosphorylations regulating PQC, the impact in cardiac pathology, and the therapeutic opportunities presented by harnessing these modifications.
    Language English
    Publishing date 2020-11-12
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2564217-0
    ISSN 1664-042X
    ISSN 1664-042X
    DOI 10.3389/fphys.2020.593585
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Transient receptor potential canonical type 6 (TRPC6) O-GlcNAcylation at Threonine-221 plays potent role in channel regulation.

    Mishra, Sumita / Ma, Junfeng / McKoy, Desirae / Sasaki, Masayuki / Farinelli, Federica / Page, Richard C / Ranek, Mark J / Zachara, Natasha / Kass, David A

    iScience

    2023  Volume 26, Issue 3, Page(s) 106294

    Abstract: Transient receptor potential canonical type 6 (TRPC6) is a non-voltage-gated channel that principally conducts calcium. Elevated channel activation contributes to fibrosis, hypertrophy, and proteinuria, often coupled to stimulation of nuclear factor of ... ...

    Abstract Transient receptor potential canonical type 6 (TRPC6) is a non-voltage-gated channel that principally conducts calcium. Elevated channel activation contributes to fibrosis, hypertrophy, and proteinuria, often coupled to stimulation of nuclear factor of activated T-cells (NFAT). TRPC6 is post-translationally regulated, but a role for O-linked β-N-acetyl glucosamine (O-GlcNAcylation) as elevated by diabetes, is unknown. Here we show TRPC6 is constitutively O-GlcNAcylated at Ser14, Thr70, and Thr221 in the N-terminus ankryn-4 (AR4) and linker (LH1) domains. Mutagenesis to alanine reveals T221 as a critical controller of resting TRPC6 conductance, and associated NFAT activity and pro-hypertrophic signaling. T→A mutations at sites homologous in closely related TRPC3 and TRPC7 also increases their activity. Molecular modeling predicts interactions between Thr221-
    Language English
    Publishing date 2023-02-28
    Publishing country United States
    Document type Journal Article
    ISSN 2589-0042
    ISSN (online) 2589-0042
    DOI 10.1016/j.isci.2023.106294
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: TSC2 S1365A mutation potently regulates CD8+ T cell function and differentiation and improves adoptive cellular cancer therapy.

    Patel, Chirag H / Dong, Yi / Koleini, Navid / Wang, Xiaoxu / Dunkerly-Eyring, Brittany L / Wen, Jiayu / Ranek, Mark J / Bartle, Laura M / Henderson, Daniel B / Sagert, Jason / Kass, David A / Powell, Jonathan D

    JCI insight

    2023  Volume 8, Issue 21

    Abstract: ... S1365 phosphorylation, and preventing this with the SA mutation markedly increased mTORC1 activation and ...

    Abstract MTORC1 integrates signaling from the immune microenvironment to regulate T cell activation, differentiation, and function. TSC2 in the tuberous sclerosis complex tightly regulates mTORC1 activation. CD8+ T cells lacking TSC2 have constitutively enhanced mTORC1 activity and generate robust effector T cells; however, sustained mTORC1 activation prevents generation of long-lived memory CD8+ T cells. Here we show that manipulating TSC2 at Ser1365 potently regulated activated but not basal mTORC1 signaling in CD8+ T cells. Unlike nonstimulated TSC2-KO cells, CD8+ T cells expressing a phosphosilencing mutant TSC2-S1365A (TSC2-SA) retained normal basal mTORC1 activity. PKC and T cell receptor (TCR) stimulation induced TSC2 S1365 phosphorylation, and preventing this with the SA mutation markedly increased mTORC1 activation and T cell effector function. Consequently, SA CD8+ T cells displayed greater effector responses while retaining their capacity to become long-lived memory T cells. SA CD8+ T cells also displayed enhanced effector function under hypoxic and acidic conditions. In murine and human solid-tumor models, SA CD8+ T cells used as adoptive cell therapy displayed greater antitumor immunity than WT CD8+ T cells. These findings reveal an upstream mechanism to regulate mTORC1 activity in T cells. The TSC2-SA mutation enhanced both T cell effector function and long-term persistence/memory formation, supporting an approach to engineer better CAR-T cells for treating cancer.
    MeSH term(s) Mice ; Humans ; Animals ; Tuberous Sclerosis ; Mechanistic Target of Rapamycin Complex 1 ; CD8-Positive T-Lymphocytes ; Mutation ; Cell Differentiation ; Tumor Microenvironment
    Chemical Substances Mechanistic Target of Rapamycin Complex 1 (EC 2.7.11.1)
    Language English
    Publishing date 2023-11-08
    Publishing country United States
    Document type Journal Article
    ISSN 2379-3708
    ISSN (online) 2379-3708
    DOI 10.1172/jci.insight.167829
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article: Targeting Protein Kinase G to Treat Cardiac Proteotoxicity.

    Oeing, Christian U / Mishra, Sumita / Dunkerly-Eyring, Brittany L / Ranek, Mark J

    Frontiers in physiology

    2020  Volume 11, Page(s) 858

    Abstract: ... hallmarks of most forms of cardiac disease, including heart failure. Their dysregulation has been shown ...

    Abstract Impaired or insufficient protein kinase G (PKG) signaling and protein quality control (PQC) are hallmarks of most forms of cardiac disease, including heart failure. Their dysregulation has been shown to contribute to and exacerbate cardiac hypertrophy and remodeling, reduced cell survival and disease pathogenesis. Enhancement of PKG signaling and PQC are associated with improved cardiac function and survival in many pre-clinical models of heart disease. While many clinically used pharmacological approaches exist to stimulate PKG, there are no FDA-approved therapies to safely enhance cardiomyocyte PQC. The latter is predominantly due to our lack of knowledge and identification of proteins regulating cardiomyocyte PQC. Recently, multiple studies have demonstrated that PKG regulates PQC in the heart, both during physiological and pathological states. These studies tested already FDA-approved pharmacological therapies to activate PKG, which enhanced cardiomyocyte PQC and alleviated cardiac disease. This review examines the roles of PKG and PQC during disease pathogenesis and summarizes the experimental and clinical data supporting the utility of stimulating PKG to target cardiac proteotoxicity.
    Language English
    Publishing date 2020-07-28
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2564217-0
    ISSN 1664-042X
    ISSN 1664-042X
    DOI 10.3389/fphys.2020.00858
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: Growth hormone-releasing hormone receptor antagonist MIA-602 attenuates cardiopulmonary injury induced by BSL-2 rVSV-SARS-CoV-2 in hACE2 mice.

    Condor Capcha, Jose M / Kamiar, Ali / Robleto, Emely / Saad, Ali G / Cui, Tengjiao / Wong, Amanda / Villano, Jason / Zhong, William / Pekosz, Andrew / Medina, Edgar / Cai, Renzhi / Sha, Wei / Ranek, Mark J / Webster, Keith A / Schally, Andrew V / Jackson, Robert M / Shehadeh, Lina A

    Proceedings of the National Academy of Sciences of the United States of America

    2023  Volume 120, Issue 48, Page(s) e2308342120

    Abstract: COVID-19 pneumonia causes acute lung injury and acute respiratory distress syndrome (ALI/ARDS) characterized by early pulmonary endothelial and epithelial injuries with altered pulmonary diffusing capacity and obstructive or restrictive physiology. ... ...

    Abstract COVID-19 pneumonia causes acute lung injury and acute respiratory distress syndrome (ALI/ARDS) characterized by early pulmonary endothelial and epithelial injuries with altered pulmonary diffusing capacity and obstructive or restrictive physiology. Growth hormone-releasing hormone receptor (GHRH-R) is expressed in the lung and heart. GHRH-R antagonist, MIA-602, has been reported to modulate immune responses to bleomycin lung injury and inflammation in granulomatous sarcoidosis. We hypothesized that MIA-602 would attenuate rVSV-SARS-CoV-2-induced pulmonary dysfunction and heart injury in a BSL-2 mouse model. Male and female K18-h
    MeSH term(s) Mice ; Male ; Female ; Animals ; SARS-CoV-2 ; COVID-19/pathology ; Lung/pathology ; Inflammation/pathology ; Respiratory Distress Syndrome/pathology ; Weight Loss ; Mice, Transgenic ; Disease Models, Animal
    Chemical Substances GHRH(1-29)NH2, (PhAc-Ada)(0)-Tyr(1), Arg(2), Fpa(5,6), Ala(8), Har(9), Tyr(Me)(10), His(11), Orn(12,) Abu(15), His(20), Orn(21), Nle(27), Arg(28), Har(29)- ; somatotropin releasing hormone receptor (F8L0ODC9D7) ; K-18 conjugate
    Language English
    Publishing date 2023-11-20
    Publishing country United States
    Document type Journal Article
    ZDB-ID 209104-5
    ISSN 1091-6490 ; 0027-8424
    ISSN (online) 1091-6490
    ISSN 0027-8424
    DOI 10.1073/pnas.2308342120
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1148: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)

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  8. Article ; Online: The role of heat shock proteins and co-chaperones in heart failure.

    Ranek, Mark J / Stachowski, Marisa J / Kirk, Jonathan A / Willis, Monte S

    Philosophical transactions of the Royal Society of London. Series B, Biological sciences

    2017  Volume 373, Issue 1738

    Abstract: The ongoing contractile and metabolic demands of the heart require a tight control over protein quality control, including the maintenance of protein folding, turnover and synthesis. In heart disease, increases in mechanical and oxidative stresses, post- ... ...

    Abstract The ongoing contractile and metabolic demands of the heart require a tight control over protein quality control, including the maintenance of protein folding, turnover and synthesis. In heart disease, increases in mechanical and oxidative stresses, post-translational modifications (e.g., phosphorylation), for example, decrease protein stability to favour misfolding in myocardial infarction, heart failure or ageing. These misfolded proteins are toxic to cardiomyocytes, directly contributing to the common accumulation found in human heart failure. One of the critical class of proteins involved in protecting the heart against these threats are molecular chaperones, including the heat shock protein70 (HSP70), HSP90 and co-chaperones CHIP (carboxy terminus of Hsp70-interacting protein, encoded by the
    MeSH term(s) Animals ; Heart Failure/genetics ; Heart Failure/physiopathology ; Heat-Shock Proteins/genetics ; Heat-Shock Proteins/metabolism ; Humans ; Mice ; Molecular Chaperones/genetics ; Molecular Chaperones/metabolism ; Myocytes, Cardiac/metabolism ; Rats
    Chemical Substances Heat-Shock Proteins ; Molecular Chaperones
    Language English
    Publishing date 2017-12-04
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 208382-6
    ISSN 1471-2970 ; 0080-4622 ; 0264-3839 ; 0962-8436
    ISSN (online) 1471-2970
    ISSN 0080-4622 ; 0264-3839 ; 0962-8436
    DOI 10.1098/rstb.2016.0530
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Einzelsignatur: Show issues

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  9. Article ; Online: TSC2 S1365A mutation potently regulates CD8+ T cell function and differentiation and improves adoptive cellular cancer therapy

    Chirag H. Patel / Yi Dong / Navid Koleini / Xiaoxu Wang / Brittany L. Dunkerly-Eyring / Jiayu Wen / Mark J. Ranek / Laura M. Bartle / Daniel B. Henderson / Jason Sagert / David A. Kass / Jonathan D. Powell

    JCI Insight, Vol 8, Iss

    2023  Volume 21

    Abstract: ... S1365 phosphorylation, and preventing this with the SA mutation markedly increased mTORC1 activation and ...

    Abstract MTORC1 integrates signaling from the immune microenvironment to regulate T cell activation, differentiation, and function. TSC2 in the tuberous sclerosis complex tightly regulates mTORC1 activation. CD8+ T cells lacking TSC2 have constitutively enhanced mTORC1 activity and generate robust effector T cells; however, sustained mTORC1 activation prevents generation of long-lived memory CD8+ T cells. Here we show that manipulating TSC2 at Ser1365 potently regulated activated but not basal mTORC1 signaling in CD8+ T cells. Unlike nonstimulated TSC2-KO cells, CD8+ T cells expressing a phosphosilencing mutant TSC2-S1365A (TSC2-SA) retained normal basal mTORC1 activity. PKC and T cell receptor (TCR) stimulation induced TSC2 S1365 phosphorylation, and preventing this with the SA mutation markedly increased mTORC1 activation and T cell effector function. Consequently, SA CD8+ T cells displayed greater effector responses while retaining their capacity to become long-lived memory T cells. SA CD8+ T cells also displayed enhanced effector function under hypoxic and acidic conditions. In murine and human solid-tumor models, SA CD8+ T cells used as adoptive cell therapy displayed greater antitumor immunity than WT CD8+ T cells. These findings reveal an upstream mechanism to regulate mTORC1 activity in T cells. The TSC2-SA mutation enhanced both T cell effector function and long-term persistence/memory formation, supporting an approach to engineer better CAR-T cells for treating cancer.
    Keywords Cell biology ; Immunology ; Medicine ; R
    Subject code 570
    Language English
    Publishing date 2023-11-01T00:00:00Z
    Publisher American Society for Clinical investigation
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  10. Article ; Online: Single serine on TSC2 exerts biased control over mTORC1 activation mediated by ERK1/2 but not Akt.

    Dunkerly-Eyring, Brittany L / Pan, Shi / Pinilla-Vera, Miguel / McKoy, Desirae / Mishra, Sumita / Grajeda Martinez, Maria I / Oeing, Christian U / Ranek, Mark J / Kass, David A

    Life science alliance

    2022  Volume 5, Issue 6

    Abstract: ... mutations. This contrasts to prior reports showing a marked impact of both on pathological pressure-stress ...

    Abstract Tuberous sclerosis complex-2 (TSC2) negatively regulates mammalian target of rapamycin complex 1 (mTORC1), and its activity is reduced by protein kinase B (Akt) and extracellular response kinase (ERK1/2) phosphorylation to activate mTORC1. Serine 1364 (human) on TSC2 bidirectionally modifies mTORC1 activation by pathological growth factors or hemodynamic stress but has no impact on resting activity. We now show this modification biases to ERK1/2 but not Akt-dependent TSC2-mTORC1 activation. Endothelin-1-stimulated mTORC1 requires ERK1/2 activation and is bidirectionally modified by phospho-mimetic (S1364E) or phospho-silenced (S1364A) mutations. However, mTORC1 activation by Akt-dependent stimuli (insulin or PDGF) is unaltered by S1364 modification. Thrombin stimulates both pathways, yet only the ERK1/2 component is modulated by S1364. S1364 also has negligible impact on mTORC1 regulation by energy or nutrient status. In vivo, diet-induced obesity, diabetes, and fatty liver couple to Akt activation and are also unaltered by TSC2 S1364 mutations. This contrasts to prior reports showing a marked impact of both on pathological pressure-stress. Thus, S1364 provides ERK1/2-selective mTORC1 control and a genetic means to modify pathological versus physiological mTOR stimuli.
    MeSH term(s) Humans ; MAP Kinase Signaling System ; Mechanistic Target of Rapamycin Complex 1/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Serine/metabolism ; Tuberous Sclerosis Complex 2 Protein/genetics ; Tuberous Sclerosis Complex 2 Protein/metabolism ; Tumor Suppressor Proteins/metabolism
    Chemical Substances Tuberous Sclerosis Complex 2 Protein ; Tumor Suppressor Proteins ; Serine (452VLY9402) ; Mechanistic Target of Rapamycin Complex 1 (EC 2.7.11.1) ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1)
    Language English
    Publishing date 2022-03-14
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ISSN 2575-1077
    ISSN (online) 2575-1077
    DOI 10.26508/lsa.202101169
    Database MEDical Literature Analysis and Retrieval System OnLINE

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