Biochemistry, Genetics and Molecular Biology › Molecular Biology

Signaling Pathways in Disease

Works Count: 29453

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Description

This cluster of papers focuses on the role of Calcineurin-NFAT signaling in transcriptional regulation, with a particular emphasis on its involvement in cancer progression, cardiac hypertrophy, and inflammatory responses. The cluster also explores the impact of Prolyl Isomerase Pin1, EMMPRIN/CD147, and immunophilins in modulating this signaling pathway.

Keywords

Calcineurin; NFAT; Transcriptional Regulation; Prolyl Isomerase Pin1; Cancer Progression; Cardiac Hypertrophy; Immunophilins; EMMPRIN/CD147; Peptidyl-Prolyl Isomerases; Inflammatory Responses

NFAT Signaling

2002-04-01

Gerald R. Crabtree , Eric N. Olson

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Calcium oscillations increase the efficiency and specificity of gene expression

1998-04-01

Ricardo E. Dolmetsch , Keli Xu , Richard S. Lewis

A human peptidyl–prolyl isomerase essential for regulation of mitosis

1996-04-01

Kun Ping Lu , Steven D. Hanes , Tony Hunter

The mitochondrial permeability transition pore and its role in cell death

1999-07-08

Martin Crompton

This article reviews the involvement of the mitochondrial permeability transition pore in necrotic and apoptotic cell death. The pore is formed from a complex of the voltage-dependent anion channel (VDAC), … This article reviews the involvement of the mitochondrial permeability transition pore in necrotic and apoptotic cell death. The pore is formed from a complex of the voltage-dependent anion channel (VDAC), the adenine nucleotide translocase and cyclophilin-D (CyP-D) at contact sites between the mitochondrial outer and inner membranes. In vitro, under pseudopathological conditions of oxidative stress, relatively high Ca2+ and low ATP, the complex flickers into an open-pore state allowing free diffusion of low-Mr solutes across the inner membrane. These conditions correspond to those that unfold during tissue ischaemia and reperfusion, suggesting that pore opening may be an important factor in the pathogenesis of necrotic cell death following ischaemia/reperfusion. Evidence that the pore does open during ischaemia/reperfusion is discussed. There are also strong indications that the VDAC-adenine nucleotide translocase-CyP-D complex can recruit a number of other proteins, including Bax, and that the complex is utilized in some capacity during apoptosis. The apoptotic pathway is amplified by the release of apoptogenic proteins from the mitochondrial intermembrane space, including cytochrome c, apoptosis-inducing factor and some procaspases. Current evidence that the pore complex is involved in outer-membrane rupture and release of these proteins during programmed cell death is reviewed, along with indications that transient pore opening may provoke ‘accidental’ apoptosis.

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The mechanism of action of cyclosporin A and FK506

1992-01-01

Stuart L. Schreiber , Robert H. Crabtree

Identification of calcineurin as a key signalling enzyme in T-lymphocyte activation

1992-06-01

Neil A. Clipstone , Robert H. Crabtree

Discovering High-Affinity Ligands for Proteins: SAR by NMR

1996-11-29

Suzanne B. Shuker , Philip J. Hajduk , Robert Meadows +1 more

A nuclear magnetic resonance (NMR)-based method is described in which small organic molecules that bind to proximal subsites of a protein are identified, optimized, and linked together to produce high-affinity … A nuclear magnetic resonance (NMR)-based method is described in which small organic molecules that bind to proximal subsites of a protein are identified, optimized, and linked together to produce high-affinity ligands. The approach is called “SAR by NMR” because structure-activity relationships (SAR) are obtained from NMR. With this technique, compounds with nanomolar affinities for the FK506 binding protein were rapidly discovered by tethering two ligands with micromolar affinities. The method reduces the amount of chemical synthesis and time required for the discovery of high-affinity ligands and appears particularly useful in target-directed drug research.

A Mammalian Histone Deacetylase Related to the Yeast Transcriptional Regulator Rpd3p

1996-04-19

Jack Taunton , Christian A. Hassig , Stuart L. Schreiber

Trapoxin is a microbially derived cyclotetrapeptide that inhibits histone deacetylation in vivo and causes mammalian cells to arrest in the cell cycle. A trapoxin affinity matrix was used to isolate … Trapoxin is a microbially derived cyclotetrapeptide that inhibits histone deacetylation in vivo and causes mammalian cells to arrest in the cell cycle. A trapoxin affinity matrix was used to isolate two nuclear proteins that copurified with histone deacetylase activity. Both proteins were identified by peptide microsequencing, and a complementary DNA encoding the histone deacetylase catalytic subunit (HD1) was cloned from a human Jurkat T cell library. As the predicted protein is very similar to the yeast transcriptional regulator Rpd3p, these results support a role for histone deacetylase as a key regulator of eukaryotic transcription.

Cyclophilin and peptidyl-prolyl cis-trans isomerase are probably identical proteins

1989-02-01

Günter Fischer , Brigitte Wittmann‐Liebold , Kurt Lang +2 more

pl Bl5: A cDNA Clone of the Rat mRNA Encoding Cyclophilin

1988-05-01

Patria E. Danielson , Sonja Forss‐Petter , Mary Ann D. Brow +4 more

We present the complete nucleotide sequence of a cDNA encoding rat cyclophilin. The 743-nucleotide sequence contains a 42-nucleotide 5′ noncoding region, a 492 nucleotide open reading frame corresponding to a … We present the complete nucleotide sequence of a cDNA encoding rat cyclophilin. The 743-nucleotide sequence contains a 42-nucleotide 5′ noncoding region, a 492 nucleotide open reading frame corresponding to a translation product of 164 amino acids with a molecular weight of 17,874, and a 3′ noncoding region of 209 nucleotides. Primer extension studies reveal the presence of one minor and two major transcription start sites. Southern blot analyses are consistent with as many as 20 copies of the cyclophilin gene and possible pseudogenes. Cyclophilin mRNA is expressed in virtually all types of tissues of rat and monkey and appears to have been highly conserved during mammalian evolution.

Ca 2+ -Induced Apoptosis Through Calcineurin Dephosphorylation of BAD

1999-04-09

Hong‐Gang Wang , Nazima Pathan , Iryna M. Ethell +7 more

The Ca 2+ -activated protein phosphatase calcineurin induces apoptosis, but the mechanism is unknown. Calcineurin was found to dephosphorylate BAD, a pro-apoptotic member of the Bcl-2 family, thus enhancing BAD … The Ca 2+ -activated protein phosphatase calcineurin induces apoptosis, but the mechanism is unknown. Calcineurin was found to dephosphorylate BAD, a pro-apoptotic member of the Bcl-2 family, thus enhancing BAD heterodimerization with Bcl-x L and promoting apoptosis. The Ca 2+ -induced dephosphorylation of BAD correlated with its dissociation from 14-3-3 in the cytosol and translocation to mitochondria where Bcl-x L resides. In hippocampal neurons, l -glutamate, an inducer of Ca 2+ influx and calcineurin activation, triggered mitochondrial targeting of BAD and apoptosis, which were both suppressible by coexpression of a dominant-inhibitory mutant of calcineurin or pharmacological inhibitors of this phosphatase. Thus, a Ca 2+ -inducible mechanism for apoptosis induction operates by regulating BAD phosphorylation and localization in cells.

A receptor for the immuno-suppressant FK506 is a cis–trans peptidyl-prolyl isomerase

1989-10-01

Matthew W. Harding , Andrzej Gałat , David Uehling +1 more

Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes

1991-08-01

Jun S. Liu , Jesse D. Farmer , Willam S. Lane +3 more

Class II Histone Deacetylases Act as Signal-Responsive Repressors of Cardiac Hypertrophy

2002-08-01

Chun Li Zhang , Timothy A. McKinsey , Shurong Chang +3 more

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Rapamycin-FKBP specifically blocks growth-dependent activation of and signaling by the 70 kd S6 protein kinases

1992-06-01

Jongkyeong Chung , Calvin J. Kuo , Gerald R. Crabtree +1 more

Induction and Activation of the Transcription Factor NFATc1 (NFAT2) Integrate RANKL Signaling in Terminal Differentiation of Osteoclasts

2002-12-01

Hiroshi Takayanagi , Sunhwa Kim , Takako Koga +7 more

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Chemistry and Biology of the Immunophilins and Their Immunosuppressive Ligands

1991-01-18

Stuart L. Schreiber

Cyclosporin A, FK506, and rapamycin are inhibitors of specific signal transduction pathways that lead to T lymphocyte activation. These immunosuppressive agents bind with high affinity to cytoplasmic receptors termed immunophilins … Cyclosporin A, FK506, and rapamycin are inhibitors of specific signal transduction pathways that lead to T lymphocyte activation. These immunosuppressive agents bind with high affinity to cytoplasmic receptors termed immunophilins (immunosuppressant binding proteins). Studies in this area have focused on the structural basis for the molecular recognition of immunosuppressants by immunophilins and the biological consequences of their interactions. Defining the biological roles of this emerging family of receptors and their ligands may illuminate the process of protein trafficking in cells and the mechanisms of signal transmission through the cytoplasm.

Apolipoprotein E controls cerebrovascular integrity via cyclophilin A

2012-05-15

Robert D. Bell , Ethan A. Winkler , Itender Singh +7 more

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Calcium's Role in Mechanotransduction during Muscle Development

2014-01-01

Tatiana Benavides Damm , Marcel Egli

Slow- and fast-twitch myofibers of adult skeletal muscles express unique sets of muscle-specific genes, and these distinctive programs of gene expression are controlled by variations in motor neuron activity. It … Slow- and fast-twitch myofibers of adult skeletal muscles express unique sets of muscle-specific genes, and these distinctive programs of gene expression are controlled by variations in motor neuron activity. It is well established that, as a consequence of more frequent neural stimulation, slow fibers maintain higher levels of intracellular free calcium than fast fibers, but the mechanisms by which calcium may function as a messenger linking nerve activity to changes in gene expression in skeletal muscle have been unknown. Here, fiber-type-specific gene expression in skeletal muscles is shown to be controlled by a signaling pathway that involves calcineurin, a cyclosporin-sensitive, calcium-regulated serine/threonine phosphatase. Activation of calcineurin in skeletal myocytes selectively up-regulates slow-fiber-specific gene promoters. Conversely, inhibition of calcineurin activity by administration of cyclosporin A to intact animals promotes slow-to-fast fiber transformation. Transcriptional activation of slow-fiber-specific transcription appears to be mediated by a combinatorial mechanism involving proteins of the NFAT and MEF2 families. These results identify a molecular mechanism by which different patterns of motor nerve activity promote selective changes in gene expression to establish the specialized characteristics of slow and fast myofibers.

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Regulation of cardiac hypertrophy by intracellular signalling pathways

2006-08-01

Joerg Heineke , Jeffery D. Molkentin

Atomic Structures of the Human Immunophilin FKBP-12 Complexes with FK506 and Rapamycin

1993-01-01

Gregory D. Van Duyne , Robert F. Standaert , P. Andrew Karplus +2 more

Intrinsic dynamics of an enzyme underlies catalysis

2005-11-01

Elan Eisenmesser , Óscar Millet , Wladimir Labeikovsky +6 more

A cytosolic binding protein for the immunosuppressant FK506 has peptidyl-prolyl isomerase activity but is distinct from cyclophilin

1989-10-01

John J. Siekierka , Shirley H.Y. Hung , Martin Poe +2 more

Nuclear association of a T-cell transcription factor blocked by FK-506 and cyclosporin A

1991-08-01

W. Michael Flanagan , Blaise Corthésy , Richard J. Bram +1 more

A mammalian protein targeted by G1-arresting rapamycin–receptor complex

1994-06-01

Eric J. Brown , Mark W. Albers , Tae Bum Shin +4 more

Peptidyl-prolyl cis-trans isomerase is the cyclosporin A-binding protein cyclophilin

1989-02-01

Nobuhiro Takahashi , Toshiya Hayano , Masanori Suzuki

Targets for Cell Cycle Arrest by the Immunosuppressant Rapamycin in Yeast

1991-08-23

Joseph Heitman , N. Rao Movva , Michael N. Hall

FK506 and rapamycin are related immunosuppressive compounds that block helper T cell activation by interfering with signal transduction. In vitro, both drugs bind and inhibit the FK506-binding protein (FKBP) proline … FK506 and rapamycin are related immunosuppressive compounds that block helper T cell activation by interfering with signal transduction. In vitro, both drugs bind and inhibit the FK506-binding protein (FKBP) proline rotamase. Saccharomyces cerevisiae cells treated with rapamycin irreversibly arrested in the G1 phase of the cell cycle. An FKBP-rapamycin complex is concluded to be the toxic agent because (i) strains that lack FKBP proline rotamase, encoded by FPR1 , were viable and fully resistant to rapamycin and (ii) FK506 antagonized rapamycin toxicity in vivo. Mutations that conferred rapamycin resistance altered conserved residues in FKBP that are critical for drug binding. Two genes other than FPR1 , named TOR1 and TOR2 , that participate in rapamycin toxicity were identified. Nonallelic noncomplementation between FPR1 , TOR1 , and TOR2 alleles suggests that the products of these genes may interact as subunits of a protein complex. Such a complex may mediate nuclear entry of signals required for progression through the cell cycle.

Cyclophilin D-dependent mitochondrial permeability transition regulates some necrotic but not apoptotic cell death

2005-03-01

Takashi Nakagawa , Shigeomi Shimizu , Tetsuya Watanabe +6 more

The Pathogenesis of Sepsis

1991-09-15

Roger C. Bone

▪Sepsis and its sequelae (sepsis syndrome and septic shock) are increasingly common and are still potentially lethal diagnoses. Many mediators of the pathogenesis of sepsis have recently been described. These … ▪Sepsis and its sequelae (sepsis syndrome and septic shock) are increasingly common and are still potentially lethal diagnoses. Many mediators of the pathogenesis of sepsis have recently been described. These include tumor necrosis factor α (TNFα), interleukins, platelet activating factor, leukotrienes, thromboxane A2, and activators of the complement cascade. Neutrophil and platelet activation may also play a role. Other agents that may participate in the sepsis cascade include adhesion molecules, kinins, thrombin, myocardial depressant substance, β-endorphin, and heat shock proteins. Endothelium-derived relaxing factor and endothelin-1 are released from the endothelium and seem to exert a regulatory effect, counterbalancing each other. A central mediator of sepsis does not seem to exist, although TNFα has been commonly proposed for this role. Animal studies are difficult to extrapolate to the clinical setting because of cross-species differences and variations in experimental design. Rather than being caused by any single pathogenic mechanism, it is more likely that sepsis is related to the state of activation of the target cell, the nearby presence of other mediators, and the ability of the target cell to release other mediators. Also important is the downregulation or negative feedback of these mediators or the generation of natural inflammation inhibitors, such as interleukin-4 and interleukin-8. Endothelial damage in sepsis probably results from persistent and repetitive inflammatory insults. Eventually, these insults produce sufficient damage that downregulation can no longer occur; this leads to a state of metabolic anarchy in which the body can no longer control its own inflammatory response.

NFAT proteins: key regulators of T-cell development and function

2005-06-01

Fernando Macián

Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death

2005-03-01

Christopher Baines , Robert A. Kaiser , Nicole H. Purcell +7 more

The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): Liver regeneration and neuronal differentiation

2003-01-27

Nabil G. Seidah , Suzanne Benjannet , L. Alexandra Wickham +6 more

Seven secretory mammalian kexin-like subtilases have been identified that cleave a variety of precursor proteins at monobasic and dibasic residues. The recently characterized pyrolysin-like subtilase SKI-1 cleaves proproteins at nonbasic … Seven secretory mammalian kexin-like subtilases have been identified that cleave a variety of precursor proteins at monobasic and dibasic residues. The recently characterized pyrolysin-like subtilase SKI-1 cleaves proproteins at nonbasic residues. In this work we describe the properties of a proteinase K-like subtilase, neural apoptosis-regulated convertase 1 (NARC-1), representing the ninth member of the secretory subtilase family. Biosynthetic and microsequencing analyses of WT and mutant enzyme revealed that human and mouse pro-NARC-1 are autocatalytically and intramolecularly processed into NARC-1 at the ( Y , I )V V (V,L)( L , M )↓ motif, a site that is representative of its enzymic specificity. In vitro peptide processing studies and/or Ala substitutions of the P1–P5 sites suggested that hydrophobic/aliphatic residues are more critical at P1, P3, and P5 than at P2 or P4. NARC-1 expression is highest in neuroepithelioma SK-N-MCIXC, hepatic BRL-3A, and in colon carcinoma LoVo-C5 cell lines. In situ hybridization and Northern blot analyses of NARC-1 expression during development in the adult and after partial hepatectomy revealed that it is expressed in cells that have the capacity to proliferate and differentiate. These include hepatocytes, kidney mesenchymal cells, intestinal ileum, and colon epithelia as well as embryonic brain telencephalon neurons. Accordingly, transfection of NARC-1 in primary cultures of embryonic day 13.5 telencephalon cells led to enhanced recruitment of undifferentiated neural progenitor cells into the neuronal lineage, suggesting that NARC-1 is implicated in the differentiation of cortical neurons.

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The regulation of transcription by phosphorylation

1992-08-01

Tony Hunter , Michael Karin

GAP-43: an intrinsic determinant of neuronal development and plasticity

1997-02-01

Larry I. Benowitz , Aryeh Routtenberg

Cyclophilin: A Specific Cytosolic Binding Protein for Cyclosporin A

1984-11-02

Robert E. Handschumacher , Matthew W. Harding , Jeffrey S. Rice +2 more

Cyclophilin, a specific cytosolic binding protein responsible for the concentration of the immunosuppressant cyclosporin A by lymphoid cells, was purified to homogeneity from bovine thymocytes. Cation-exchange high-performance liquid chromatography resolved … Cyclophilin, a specific cytosolic binding protein responsible for the concentration of the immunosuppressant cyclosporin A by lymphoid cells, was purified to homogeneity from bovine thymocytes. Cation-exchange high-performance liquid chromatography resolved a major and minor cyclophilin species that bind cyclosporin A with a dissociation constant of about 2 × 10 -7 moles per liter and specific activities of 77 and 67 micrograms per milligram of protein, respectively. Both cyclophilin species have an apparent molecular weight of 15,000, an isoelectric point of 9.6, and nearly identical amino acid compositions. A portion of the NH 2 -terminal amino acid sequence of the major species was determined. The cyclosporin A-binding activity of cyclophilin is sulfhydryl dependent, unstable at 56°C and at p H 4 or 9.5, and sensitive to trypsin but not to chymotrypsin digestion. Cyclophilin specifically binds a series of cyclosporin analogs in proportion to their activity in a mixed lymphocyte reaction. Isolation of cyclophilin from the cytosol of thymocytes suggests that the immunosuppressive activity of cyclosporin A is mediated by an intracellular mechanism, not by a membrane-associated mechanism.

Bmi-1 collaborates with c-Myc in tumorigenesis by inhibiting c-Myc-induced apoptosis via INK4a/ARF

1999-10-15

Jacqueline J.L. Jacobs , Blanca Scheijen , Jan Willem Voncken +3 more

The bmi-1 and myc oncogenes collaborate strongly in murine lymphomagenesis, but the basis for this collaboration was not understood. We recently identified the ink4a-ARF tumor suppressor locus as a critical … The bmi-1 and myc oncogenes collaborate strongly in murine lymphomagenesis, but the basis for this collaboration was not understood. We recently identified the ink4a-ARF tumor suppressor locus as a critical downstream target of the Polycomb-group transcriptional repressor Bmi-1. Others have shown that part of Myc's ability to induce apoptosis depends on induction of p19arf. Here we demonstrate that down-regulation of ink4a-ARF by Bmi-1 underlies its ability to cooperate with Myc in tumorigenesis. Heterozygosity for bmi-1 inhibits lymphomagenesis in Emu-myc mice by enhancing c-Myc-induced apoptosis. We observe increased apoptosis in bmi-1(-/-) lymphoid organs, which can be rescued by deletion of ink4a-ARF or overexpression of bcl2. Furthermore, Bmi-1 collaborates with Myc in enhancing proliferation and transformation of primary embryo fibroblasts (MEFs) in an ink4a-ARF dependent manner, by prohibiting Myc-mediated induction of p19arf and apoptosis. We observe strong collaboration between the Emu-myc transgene and heterozygosity for ink4a-ARF, which is accompanied by loss of the wild-type ink4a-ARF allele and formation of highly aggressive B-cell lymphomas. Together, these results reinforce the critical role of Bmi-1 as a dose-dependent regulator of ink4a-ARF, which on its turn acts to prevent tumorigenesis on activation of oncogenes such as c-myc.

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RAFT1: A mammalian protein that binds to FKBP12 in a rapamycin-dependent fashion and is homologous to yeast TORs

1994-07-01

David M. Sabatini , Hediye Erdjument‐Bromage , Mary Lui +2 more

TRANSCRIPTIONAL CONTROL OF MUSCLE DEVELOPMENT BY MYOCYTE ENHANCER FACTOR-2 (MEF2) PROTEINS

1998-11-01

Brian L. Black , Eric N. Olson

▪ Abstract Metazoans contain multiple types of muscle cells that share several common properties, including contractility, excitability, and expression of overlapping sets of muscle structural genes that mediate these functions. … ▪ Abstract Metazoans contain multiple types of muscle cells that share several common properties, including contractility, excitability, and expression of overlapping sets of muscle structural genes that mediate these functions. Recent biochemical and genetic studies have demonstrated that members of the myocyte enhancer factor-2 (MEF2) family of MADS (MCM1, agamous, deficiens, serum response factor)-box transcription factors play multiple roles in muscle cells to control myogenesis and morphogenesis. Like other MADS-box proteins, MEF2 proteins act combinatorially through protein-protein interactions with other transcription factors to control specific sets of target genes. Genetic studies in Drosophila have also begun to reveal the upstream elements of myogenic regulatory hierarchies that control MEF2 expression during development of skeletal, cardiac, and visceral muscle lineages. Paradoxically, MEF2 factors also regulate cell proliferation by functioning as endpoints for a variety of growth factor-regulated intracellular signaling pathways that are antagonistic to muscle differentiation. We discuss the diverse functions of this family of transcription factors, the ways in which they are regulated, and their mechanisms of action.

PKA Phosphorylation Dissociates FKBP12.6 from the Calcium Release Channel (Ryanodine Receptor)

2000-05-01

Steven O. Marx , Steven Reiken , Yuji Hisamatsu +4 more

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TRANSCRIPTION FACTORS OF THE NFAT FAMILY:Regulation and Function

1997-04-01

Anjana Rao , Chun Huai Luo , Patrick G. Hogan

▪ Abstract As targets for the immunosuppressive drugs cyclosporin A and FK506, transcription factors of the NFAT (nuclear factor of activated T cells) family have been the focus of much … ▪ Abstract As targets for the immunosuppressive drugs cyclosporin A and FK506, transcription factors of the NFAT (nuclear factor of activated T cells) family have been the focus of much attention. NFAT proteins, which are expressed in most immune-system cells, play a pivotal role in the transcription of cytokine genes and other genes critical for the immune response. The activity of NFAT proteins is tightly regulated by the calcium/calmodulin-dependent phosphatase calcineurin, a primary target for inhibition by cyclosporin A and FK506. Calcineurin controls the translocation of NFAT proteins from the cytoplasm to the nucleus of activated cells by interacting with an N-terminal regulatory domain conserved in the NFAT family. The DNA-binding domains of NFAT proteins resemble those of Rel-family proteins, and Rel and NFAT proteins show some overlap in their ability to bind to certain regulatory elements in cytokine genes. NFAT is also notable for its ability to bind cooperatively with transcription factors of the AP-1 (Fos/Jun) family to composite NFAT:AP-1 sites, found in the regulatory regions of many genes that are inducibly transcribed by immune-system cells. This review discusses recent data on the diversity of the NFAT family of transcription factors, the regulation of NFAT proteins within cells, and the cooperation of NFAT proteins with other transcription factors to regulate the expression of inducible genes.

Signal transduction by lymphocyte antigen receptors

1994-01-01

Arthur Weiss , Dan R. Littman

A calcineurin-dependent transcriptional pathway controls skeletal muscle fiber type

1998-08-15

Eva R. Chin , Eric N. Olson , James A. Richardson +7 more

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A Calcineurin-Dependent Transcriptional Pathway for Cardiac Hypertrophy

1998-04-01

Jeffery D. Molkentin , Jianrong Lu , Christopher L. Antos +5 more

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Transcriptional regulation by calcium, calcineurin, and NFAT

2003-09-15

Patrick G. Hogan , Lin Chen , Julie Nardone +1 more

The NFAT family of transcription factors encompasses five proteins evolutionarily related to the Rel/NF B family (Chytil and Verdine 1996; Graef et al. 2001b). The primordial family member is NFAT5, … The NFAT family of transcription factors encompasses five proteins evolutionarily related to the Rel/NF B family (Chytil and Verdine 1996; Graef et al. 2001b). The primordial family member is NFAT5, the only NFATrelated protein represented in the Drosophila genome. NFAT5 is identical to TonEBP (tonicity element binding protein), a transcription factor crucial for cellular responses to hypertonic stress (Lopez-Rodriguez et al. 1999; Miyakawa et al. 1999). We focus here on the remaining four NFAT proteins (NFAT1–NFAT4, also known as NFATc1–c4; see Table 1), referring to them collectively as NFAT. The distinguishing feature of NFAT is its regulation by Ca and the Ca/calmodulin-dependent serine phosphatase calcineurin. NFAT proteins are phosphorylated and reside in the cytoplasm in resting cells; upon stimulation, they are dephosphorylated by calcineurin, translocate to the nucleus, and become transcriptionally active, thus providing a direct link between intracellular Ca signaling and gene expression. NFAT activity is further modulated by additional inputs from diverse signaling pathways, which affect NFAT kinases and nuclear partner proteins. In the first part of this review, we describe the influence of these multiple inputs on the nuclear–cytoplasmic distribution and transcriptional function of NFAT. Recent structural data emphasize the remarkable versatility of NFAT binding to DNA. At composite NFAT:AP-1 elements found in the regulatory regions of many target genes, NFAT proteins bind cooperatively with an unrelated transcription factor, AP-1 (Fos–Jun; Chen et al. 1998). At DNA elements that resemble NF B sites, NFAT proteins bind DNA as dimers (Giffin et al. 2003; Jin et al. 2003). In the second section of this review, we describe these two modes of DNA binding by NFAT. NFAT also acts synergistically with transcription factors other than Fos and Jun, but the structural basis for synergy remains unknown. Drawing on published structures, we discuss the potential cooperation of NFAT with other classes of DNA-binding proteins. It is clear that NFAT activates transcription of a large number of genes during an effective immune response (Rao et al. 1997; Kiani et al. 2000; Serfling et al. 2000; Macian et al. 2001). In the third part of this review, we present information obtained from these studies, highlighting experimental and bioinformatics approaches to identifying NFAT target genes. We discuss the finding that NFAT and NFAT–Fos–Jun complexes activate distinct subsets of target genes in lymphocytes (Macian et al. 2002). We also describe a novel aspect of gene regulation by NFAT, in which this transcription factor participates in an early phase of chromatin remodeling that occurs at specific genetic loci in differentiating T cells (Avni et al. 2002). There is evidence that NFAT regulates cell differentiation programs in cell types other than immune cells (Crabtree and Olson 2002; Horsley and Pavlath 2002; Graef et al. 2003; Hill-Eubanks et al. 2003). In the last section of this review, we select three differentiation programs—fiber-type specification in differentiated skeletal muscle, cardiac valve development, and osteoclast differentiation—for detailed consideration. We evaluate the evidence for NFAT involvement, point out novel cellular and molecular mechanisms that might regulate this familiar transcription factor, and discuss how NFAT exerts its biological effects. Because the phenotypes of NFAT knockout mice have been reviewed elsewhere (Crabtree and Olson 2002; Horsley and Pavlath 2002), we refer to them only as necessary to illustrate specific points.

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Isolation and Characterization of GBP28, a Novel Gelatin-Binding Protein Purified from Human Plasma

1996-10-01

Yasuko Nakano , Takashi Tobe , N.-H. Choi-Miura +2 more

By use of its affinity to gelatin-Cellulofine, a novel protein, GBP28 (gelatin-binding protein of 28 kDa), was obtained from human plasma. GBP28 bound to gelatin-Cellulofine could be eluted with 1 … By use of its affinity to gelatin-Cellulofine, a novel protein, GBP28 (gelatin-binding protein of 28 kDa), was obtained from human plasma. GBP28 bound to gelatin-Cellulofine could be eluted with 1 M NaCl. By analysis of its amino-terminal amino acid sequences and the peptides obtained by protease digestion, GBP28 was identified as a novel protein. After repeated gel chromatography of the 1 M NaCl eluate from gelatin-Cellulofine, about 50 μg of GBP28 was purified from 500 ml of human plasma. On gel chromatography, the protein migrated as a molecule of about 420 kDa. On SDS-PAGE, its molecular mass was 28 kDa under reducing conditions and 68 kDa under nonreducing conditions. Recently, human mRNA specific to adipose tissue, cDNA clone apM1, has been registered [Maeda, K., Okubo, K., Shimomura, I., Funahashi, T., Matsuzawa, Y., and Matsubara, K. (1996) Biochem. Biophys. Res. Commun. 221, 286–289]. The assumed amino acid sequence of cDNA clone apM1 contained all the sequences of GBP28 and its peptides. Therefore, it is evident that the cDNA clone apM1 encodes GBP28 and the protein is specific to adipose tissue. The clone encodes a polypeptide of 244 amino acids with a secretory signal sequence at the amino terminus, a small non-helical region, a stretch of 22 collagen repeats and a globular domain. Thus, GBP28 appears to belong to a family of proteins possessing a collagen-like domain through which they form homo-trimers, which further combine to make oligomeric complexes. Although its biological function is presently unclear, its adipocyte-specific expression suggests that GBP28 may function as an endogenous factor involved in lipid catabolism and storage or whole body metabolism.

Regulation of translation initiation by FRAP/mTOR

2001-04-01

Anne‐Claude Gingras , Brian Raught , Nahum Sonenberg

Calcineurin: Form and Function

2000-01-10

Frank Rusnak , Pamela Mertz

Calcineurin is a eukaryotic Ca 2+ - and calmodulin-dependent serine/threonine protein phosphatase. It is a heterodimeric protein consisting of a catalytic subunit calcineurin A, which contains an active site dinuclear … Calcineurin is a eukaryotic Ca 2+ - and calmodulin-dependent serine/threonine protein phosphatase. It is a heterodimeric protein consisting of a catalytic subunit calcineurin A, which contains an active site dinuclear metal center, and a tightly associated, myristoylated, Ca 2+ -binding subunit, calcineurin B. The primary sequence of both subunits and heterodimeric quaternary structure is highly conserved from yeast to mammals. As a serine/threonine protein phosphatase, calcineurin participates in a number of cellular processes and Ca 2+ -dependent signal transduction pathways. Calcineurin is potently inhibited by immunosuppressant drugs, cyclosporin A and FK506, in the presence of their respective cytoplasmic immunophilin proteins, cyclophilin and FK506-binding protein. Many studies have used these immunosuppressant drugs and/or modern genetic techniques to disrupt calcineurin in model organisms such as yeast, filamentous fungi, plants, vertebrates, and mammals to explore its biological function. Recent advances regarding calcineurin structure include the determination of its three-dimensional structure. In addition, biochemical and spectroscopic studies are beginning to unravel aspects of the mechanism of phosphate ester hydrolysis including the importance of the dinuclear metal ion cofactor and metal ion redox chemistry, studies which may lead to new calcineurin inhibitors. This review provides a comprehensive examination of the biological roles of calcineurin and reviews aspects related to its structure and catalytic mechanism.

The Role of the CD28 Receptor During T Cell Responses to Antigen

1993-04-01

P S Linsley , J A Ledbetter

Exhausted CD8 T (Tex) cells are a distinct cell lineage that arise during chronic infections and cancers in animal models and humans. Tex cells are characterized by progressive loss of … Exhausted CD8 T (Tex) cells are a distinct cell lineage that arise during chronic infections and cancers in animal models and humans. Tex cells are characterized by progressive loss of effector functions, high and sustained inhibitory receptor expression, ...Read More

CD147-spike protein is a novel route for SARS-CoV-2 infection to host cells

2020-12-04

Ke Wang , Wei Chen , Zheng Zhang +7 more

Abstract In face of the everlasting battle toward COVID-19 and the rapid evolution of SARS-CoV-2, no specific and effective drugs for treating this disease have been reported until today. Angiotensin-converting … Abstract In face of the everlasting battle toward COVID-19 and the rapid evolution of SARS-CoV-2, no specific and effective drugs for treating this disease have been reported until today. Angiotensin-converting enzyme 2 (ACE2), a receptor of SARS-CoV-2, mediates the virus infection by binding to spike protein. Although ACE2 is expressed in the lung, kidney, and intestine, its expressing levels are rather low, especially in the lung. Considering the great infectivity of COVID-19, we speculate that SARS-CoV-2 may depend on other routes to facilitate its infection. Here, we first discover an interaction between host cell receptor CD147 and SARS-CoV-2 spike protein. The loss of CD147 or blocking CD147 in Vero E6 and BEAS-2B cell lines by anti-CD147 antibody, Meplazumab, inhibits SARS-CoV-2 amplification. Expression of human CD147 allows virus entry into non-susceptible BHK-21 cells, which can be neutralized by CD147 extracellular fragment. Viral loads are detectable in the lungs of human CD147 (hCD147) mice infected with SARS-CoV-2, but not in those of virus-infected wild type mice. Interestingly, virions are observed in lymphocytes of lung tissue from a COVID-19 patient. Human T cells with a property of ACE2 natural deficiency can be infected with SARS-CoV-2 pseudovirus in a dose-dependent manner, which is specifically inhibited by Meplazumab. Furthermore, CD147 mediates virus entering host cells by endocytosis. Together, our study reveals a novel virus entry route, CD147-spike protein, which provides an important target for developing specific and effective drug against COVID-19.

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Cyclosporine

1989-12-21

John A. Oates , Alastair J.J. Wood , Barry D. Kahan

ATHERAPEUTIC attack on the immune system is initiated in anticipation of or in response to immunologically mediated tissue damage. Drug regimens seek to inhibit selectively the T-cell and B-cell elements … ATHERAPEUTIC attack on the immune system is initiated in anticipation of or in response to immunologically mediated tissue damage. Drug regimens seek to inhibit selectively the T-cell and B-cell elements that permit adaptive, specific recognition of pathogenic, alien molecules and organisms while sparing the nonspecific granulocyte, monocyte, and macrophage elements that are responsible for phagocytosis, digestion, and metabolism of foreign materials. The prototype immunosuppressive drugs — azathioprine and adrenal corticosteroids — inhibit cell division of and cytokine generation by all elements of the immune system, respectively. In contradistinction, the immunosuppressive agent cyclosporine selectively inhibits adaptive immune responses. In spite of . . .

Inhibiting myosin in glioblastoma

2025-06-24

Sarah Crunkhorn | Nature Reviews Drug Discovery

Covalent Inhibition of the Peptidyl‐Prolyl Isomerase Pin1 by Sulfopin Results in a Broad Impact on the Phosphoproteome of Human Osteosarcoma U2‐OS Cells

2025-06-23

Scott E. Roffey , Owen Hovey , Kristina Jurčić +3 more | PROTEOMICS

ABSTRACT Peptidyl‐prolyl isomerase, NIMA‐interacting protein 1‐(Pin1) catalyses the cis – trans interconversion of the inflexible bond between serine or threonine residues and proline at the +1 position (pSer/pThr‐Pro). Although initially … ABSTRACT Peptidyl‐prolyl isomerase, NIMA‐interacting protein 1‐(Pin1) catalyses the cis – trans interconversion of the inflexible bond between serine or threonine residues and proline at the +1 position (pSer/pThr‐Pro). Although initially discovered as an essential regulator of cell division, Pin1 has since been identified as a regulator of many biological processes and is associated with numerous malignancies and neurodegenerative disorders. Pin1 has been shown to influence phosphorylation by modulating phosphatase accessibility. However, it can also indirectly regulate phosphorylation by isomerizing peptidyl‐prolyl bonds on kinases, affecting their subcellular localization and/or substrate specificity. Here, SILAC‐based mass spectrometry was employed to identify proteomic and phosphoproteomic changes in human osteosarcoma human osteosarcoma cell line (U2‐OS) cells in response to treatment with the selective covalent Pin1 inhibitor Sulfopin. We confirmed that Sulfopin covalently binds Pin1 and profiled Pin1‐dependent changes to the proteome and phosphoproteome, identifying 803 phosphosites that underwent significant Sulfopin‐dependent changes. The identified phosphosites include substrates for a number of distinct kinases, including protein kinase B (AKT1), aurora kinase A (AURKA), cyclin‐dependent kinase (CDK)1 and CK2. Overall, this study reveals the broad impact of Sulfopin on the phosphoproteome, improving our understanding of how Pin1 modulates complex regulatory kinase networks in living cells. Summary The peptidyl‐prolyl isomerase (PPIase) Pin1 has emerged as a potential therapeutic target for numerous malignancies and neurodegenerative disorders based on its altered expression in several diseases. As the activity of Pin1 is phosphorylation‐dependent, it is intimately involved with constituents of regulatory kinase networks within cells. To elucidate how Pin1 orchestrates regulatory signalling within cells, we performed quantitative proteomic and phosphoproteomic profiling of SILAC‐labelled human osteosarcoma U2‐OS cells treated with Sulfopin, a highly selective covalent Pin1 inhibitor. In addition to demonstrating that Pin1 inhibition alters the abundance and phosphorylation of proteins involved in a variety of fundamental cellular processes, these studies revealed that Pin1 inhibition modulates the phosphorylation of 803 phosphorylation sites, ultimately improving our understanding of how a PPIase regulates phosphorylation networks in complex biological systems.

The ADAMTS2 metalloproteinase inhibits tumor growth by regulating the innate immune system

2025-06-23

Loïc Joannes , Laura Dupont , Louis Stock +7 more | Cancer Cell International

Ca2+ microdomain-based excitation-transcription coupling in cardiac myocytes and vascular smooth muscle cells

2025-06-23

Tsukasa Koide , Wayne R. Giles , Rubii Kondo +3 more | Inflammation and Regeneration

Calcineurin targets that mediate Cryptococcus thermotolerance

2025-06-23

Aaron P. Mitchell | Proceedings of the National Academy of Sciences

Author Correction: CD147 regulates the Rap1 signaling pathway to promote proliferation, migration, and invasion, and inhibit apoptosis in colorectal cancer cells

2025-06-20

Xiaoxia Fu , Rui Li , Chen Meiru +2 more | Scientific Reports

Wnt/Ca2+ signaling: Dichotomous roles in regulating tumor progress (Review)

2025-06-18

Jing Liu , Hui Wang , Sheng Xia +1 more | Oncology Letters

Editor’s Note: Recombinant Immunoproapoptotic Proteins with Furin Site Can Translocate and Kill HER2-Positive Cancer Cells

2025-06-16

Tao Wang , Jing Zhao , Jun Ren +7 more | Cancer Research

Correction to: ATP13A2/PARK9 regulates endo-/lysosomal cargo sorting and proteostasis through a novel PI(3, 5)P2-mediated scaffolding function

2025-06-16

| Human Molecular Genetics

CLEC5A suppresses cell growth and metastasis via interfering with the calcineurin/NFATc1 signaling pathway in osteosarcoma

2025-06-14

Bin Hu , Ruifeng Shi , Xiangan Kong +4 more | Experimental Cell Research

FKBP5 promotes osteogenic differentiation of mesenchymal stem cells through type-I interferon pathway Inhibition

2025-06-14

Jun Tang , Ming Li , Yuanquan Chen +7 more | Cellular and Molecular Life Sciences

The decreased osteogenesis of bone marrow mesenchymal stem cells (BMSCs) is an important factor causing bone loss. Nevertheless, its deep molecular mechanism has still not been fully clarified. To elucidate … The decreased osteogenesis of bone marrow mesenchymal stem cells (BMSCs) is an important factor causing bone loss. Nevertheless, its deep molecular mechanism has still not been fully clarified. To elucidate the regulatory mechanisms underlying BMSC osteogenesis, we conducted a bioinformatics screen using public datasets from the Gene Expression Omnibus (GEO) database to identify genes displaying significant expression dynamics during the osteogenic differentiation of BMSCs. We observed a significant upregulation of FK506 Binding Protein 5 (FKBP5) expression during the osteogenic differentiation of BMSCs. Besides, knockdown and overexpression of FKBP5 could reduce and increase osteogenic markers and Alizarin Red S (ARS) staining, respectively. Enrichment analysis of RNA sequencing (RNA-seq) demonstrated that downregulation of FKBP5 activated IFNα/β signaling pathway. FKBP5 overexpression relieved the inhibitory effect of IFNβ on osteogenesis. In addition, one of the upregulated interferon-stimulated genes (ISG), interferon-induced protein with tetratricopeptide repeats 2 (IFIT2), negatively regulated osteogenesis of BMSCs. IFIT2 knockdown rescued negative effect on osteogenesis caused by downregulation of FKBP5. Hydroxyapatite scaffold implanted in nude mice and drilled tibiae model in C57BL/6 mice confirmed positive role of FKBP5 in osteogenesis in vivo. Therefore, we determined the beneficial effect of FKBP5 on osteogenesis of BMSCs and validated the critical role of FKBP5/IFIT2 axis in this process. These findings might contribute to comprehension and treatment of bone diseases, like osteoporosis and bone fracture.

RCAN1-Mediated Calcineurin Impairment Drives Sympathetic Outflow in Hypertension

2025-06-13

Jingjing Zhou , Jian-Ying Shao , Shao-Rui Chen +2 more | Circulation Research

BACKGROUND: Calcineurin activity in the hypothalamic paraventricular nucleus (PVN) constitutively suppresses sympathetic output by tonically inhibiting glutamate NMDARs ( N -methyl-D-aspartate receptors). Clinically used calcineurin inhibitors diminish calcineurin activity in … BACKGROUND: Calcineurin activity in the hypothalamic paraventricular nucleus (PVN) constitutively suppresses sympathetic output by tonically inhibiting glutamate NMDARs ( N -methyl-D-aspartate receptors). Clinically used calcineurin inhibitors diminish calcineurin activity in the PVN, leading to persistent overactivation of the sympathetic nervous system. In this study, we investigated the role of calcineurin signaling in the PVN in sympathetic overactivity in spontaneously hypertensive rats (SHR), a widely used genetic model for essential hypertension. METHODS AND RESULTS: Calcineurin phosphatase activity in the PVN and other forebrain regions was much lower in SHR than in normotensive Wistar-Kyoto rats (WKY). However, systemic treatment with angiotensin II had no significant effect on brain calcineurin activity. Radiotelemetry recordings showed that systemic administration of tacrolimus (FK506), a specific calcineurin inhibitor, induced persistent hypertension in WKY but did not affect the already elevated arterial blood pressure in SHR. Also, microinjection of FK506 into the PVN significantly increased renal sympathetic nerve activity and arterial blood pressure in WKY but had no effect on SHR. Furthermore, coimmunoprecipitation assays and whole-cell patch-clamp recording in brain slices revealed that FK506 treatment increased α2δ-1–NMDAR interactions and synaptic NMDAR activity in spinally projecting PVN neurons in WKY but not in SHR. Blocking NMDARs with memantine or inhibiting α2δ-1 with gabapentin substantially reduced elevated arterial blood pressure in both FK506-treated WKY and SHR. Despite comparable levels of calcineurin-NMDAR complexes in the PVN of WKY and SHR, the interaction between calcineurin and RCAN1 (regulator of calcineurin 1, also known as calcipressin-1 or DSCR1 [Down syndrome critical region 1]), an endogenous calcineurin inhibitor, was significantly increased in SHR. Coimmunoprecipitation analyses showed that serine phosphorylation of RCAN1 in the PVN was much greater in SHR than in WKY. Disrupting RCAN1-calcineurin interactions using an RCAN1 C terminus peptide reversed synaptic NMDAR hyperactivity in spinally projecting PVN neurons in SHR. In addition, microinjection of the RCAN1 C terminus peptide into the PVN attenuated renal sympathetic nerve activity and arterial blood pressure in SHR. CONCLUSIONS: RCAN1-mediated calcineurin inhibition in the PVN augments sympathetic outflow by promoting synaptic expression and activity of α2δ-1–bound NMDARs in SHR. These findings identify a novel molecular mechanism underlying sympathetic overactivity in genetic hypertension and suggest potential therapeutic targets for neurogenic hypertension.

Selective interaction of the protein SMCHD1 with specific chromatin regions is governed by the loading factor LRIF1 and SMCHD1 ATPase activity

2025-06-13

Flavia Constantinescu , Aleksander Szczurek , Tatyana B. Nesterova +5 more | bioRxiv (Cold Spring Harbor Laboratory)

The chromosomal protein SMCHD1 is a GHKL ATPase that plays important roles in epigenetic silencing, including on the inactive X chromosome (Xi) and at the D4Z4 macrosatellite linked to regulation … The chromosomal protein SMCHD1 is a GHKL ATPase that plays important roles in epigenetic silencing, including on the inactive X chromosome (Xi) and at the D4Z4 macrosatellite linked to regulation of DUX4 expression in the disorders facioscapulohumeral muscular dystrophy (FSHD2) and Bosma arrhinia micropthalmia syndrome (BAMS). In this study we use live-cell and single-molecule imaging approaches to investigate SMCHD1 interactions with chromatin and its function in epigenetic silencing. We show that chromatin binding of SMCHD1 genome-wide, including on the Xi, is critically dependent on the protein LRIF1 that mediates interaction with H3K9me2/3 modified nucleosomes. Using engineered mutations in the GHKL ATPase domain we show that ATP hydrolysis is required for selective enrichment of SMCHD1 at specific chromatin regions, which is critical for gene silencing on the Xi. A gain-of-function mutation, G137E, that occurs in BAMS patients, results in accelerated Xi recruitment and greater Xi chromosome compaction. Together, our findings advance mechanistic understanding of SMCHD1 function on the Xi and at other target sites in the genome.

1828-P: STIM1 Deficiency Impairs Glucose Regulation by Altering Insulin Granules, Mitochondria, and Endoplasmic Reticulum Ultrastructure in Beta Cells

2025-06-13

Tatsuyoshi Kono , Madeline R. McLaughlin , Paul Sohn +6 more | Diabetes

Introduction and Objective: Impairments in endoplasmic reticulum (ER) calcium (Ca2+) homeostasis are associated with β cell dysfunction and the development of diabetes. Store-operated Ca2+ entry (SOCE) replenishes ER Ca2+ stores … Introduction and Objective: Impairments in endoplasmic reticulum (ER) calcium (Ca2+) homeostasis are associated with β cell dysfunction and the development of diabetes. Store-operated Ca2+ entry (SOCE) replenishes ER Ca2+ stores via plasma membrane Ca2+ channels that are regulated by the ER Ca2+ sensor stromal interaction molecule 1 (STIM1). We have previously shown that female mice with β cell-specific STIM1 (STIM1Δβ) deletion exhibit reduced β cell mass, increased α cell mass, and diminished β cell maturity markers. Furthermore, RNAseq analysis on islets from control and STIM1Δβ female mice revealed 55 significantly modulated pathways, including “mitochondrial dysfunction” and “endocytosis.” Here, we sought to determine the effect of STIM1 deletion on mitochondrial function, insulin granule maturation, and ER architecture. Methods: Mitochondrial function was evaluated using morphology analysis and a RIP-promotor controlled-Mito CEPIA. Insulin granule maturation was determined using syncollin-dsRedE5TIMER (a fluorescent time construct) and TEM analysis. Lastly, expansion microscopy (ExM) and single molecule localization microscopy (SMLM) was used to determine ER architecture. Results: We found abnormal morphology and impaired mitochondrial Ca2+ levels in STIM1 KO compared to WT INS-1 cells. Analysis with syncollin-dsRedE5TIMER showed accumulation of old insulin granules in STIM1 KO cells, and TEM revealed a significant increase in the ratio of immature to mature granules and a reduction in granule halo size in islets from STIM1Δβ female mice. Lastly, ExM and SMLM revealed a significant reduction in tubule diameter in STIM1 KO cells under ER stress, and STIM1 KO cells exhibited further decreases in tubule diameter in ER regions distal to the nucleus. Conclusion: Our findings link STIM1 loss to alterations in mitochondrial morphology, insulin granule maturation, and ER ultrastructure that may impair β cell function. Disclosure T. Kono: None. M. McLaughlin: None. P. Sohn: None. P. Krishnan: None. W. Wu: None. C. Lee: None. F. Huang: None. M. Slak Rupnik: None. C. Evans-Molina: Advisory Panel; DiogenX. Research Support; Bristol-Myers Squibb Company, Lilly Diabetes. Advisory Panel; Isla Technologies, Neurodon. Research Support; Neurodon. Funding U.S. Department of Veterans Affairs Merit Award (I01BX001733)

Molecular screening in a translational large animal trial identifies a differential inflammatory response for MINOCA

2025-06-13

Jasper Iske , Joshua M. Mesfin , Petra Wolint +7 more | Basic Research in Cardiology

Transcriptional signature of cardiac myocyte recovery in mice and human reveals persistent upregulation of epigenetic factors

2025-06-05

Richard B. Roth , Margareta Häckh , Tilman Schnick +7 more | Epigenetics

Fibrosis, cardiac remodelling, and inflammation are hallmarks of heart failure. To date, there is no available pharmacological cure for heart failure, but mechanical unloading by implantation of a left ventricular … Fibrosis, cardiac remodelling, and inflammation are hallmarks of heart failure. To date, there is no available pharmacological cure for heart failure, but mechanical unloading by implantation of a left ventricular assist device (LVAD) can lead to improved cardiac function in a subset of patients. This study aimed to identify the transcriptional response of left ventricular (LV) cardiac myocytes to mechanical unloading in a mouse model of reversible LV pressure overload and in failing human hearts after LVAD implantation. We found that partial recovery of ventricular dysfunction, LV hypertrophy, and gene expression programmes occurred in mice under reversible transverse aortic constriction (rTAC). Gene expression analysis in cardiac myocytes identified a lasting repression of mitochondrial gene expression resulting in compromised fatty acid oxidation in the mouse model of reversible pressure overload and in human LV samples after LVAD therapy and a persistent upregulation of epigenetic and transcriptional regulators. These findings underpin that recovery from heart failure involves complex gene regulatory networks and that mitochondrial dysfunction remains a challenge even after mechanical unloading. Further studies are needed to investigate the functional role of these factors in reverse remodelling and recovery of failing hearts.

Relationship Between Activating Transcription Factor 3 and Forkhead Box Protein A2 in Spinal Cord Injury and the Underlying Mechanism

2025-06-04

Xiong Dong , Hua Gu , Guanhua Xu +2 more | Applied Biochemistry and Biotechnology