LMNA-linked lipodystrophies: from altered fat distribution to cellular alterations

2011 ◽  
Vol 39 (6) ◽  
pp. 1752-1757 ◽  
Author(s):  
Guillaume Bidault ◽  
Camille Vatier ◽  
Jacqueline Capeau ◽  
Corinne Vigouroux ◽  
Véronique Béréziat
Keyword(s):  
Regulatory Element ◽  
Fat Distribution ◽  
Premature Aging ◽  
Mitogen Activated Protein Kinase ◽  
Metabolic Disturbances ◽  
Gene Encoding ◽  
Partial Lipodystrophy ◽  
Metabolic Alterations ◽  
Mitogen Activated Protein ◽  
Cellular Alterations

Mutations in the LMNA gene, encoding the nuclear intermediate filaments the A-type lamins, result in a wide variety of diseases known as laminopathies. Some of them, such as familial partial lipodystrophy of Dunnigan and metabolic laminopathies, are characterized by lipodystrophic syndromes with altered fat distribution and severe metabolic alterations with insulin resistance and dyslipidaemia. Metabolic disturbances could be due either to the inability of adipose tissue to adequately store triacylglycerols or to other cellular alterations linked to A-type lamin mutations. Indeed, abnormal prelamin A accumulation and farnesylation, which are clearly involved in laminopathic premature aging syndromes, could play important roles in lipodystrophies. In addition, gene expression alterations, and signalling abnormalities affecting SREBP1 (sterol-regulatory-element-binding protein 1) and MAPK (mitogen-activated protein kinase) pathways, could participate in the pathophysiological mechanisms leading to LMNA (lamin A/C)-linked metabolic alterations and lipodystrophies. In the present review, we describe the clinical phenotype of LMNA-linked lipodystrophies and discuss the current physiological and biochemical hypotheses regarding the pathophysiology of these diseases.

Structural diseases of the heart: syndromes affecting the cardiovascular system

ESC CardioMed ◽  
2018 ◽  
pp. 719-722
Author(s):  
Sabine Klaassen
Keyword(s):  
Single Gene ◽  
Significant Proportion ◽  
Signal Transduction Pathway ◽  
Alagille Syndrome ◽  
Mitogen Activated Protein Kinase ◽  
Neurological Deficits ◽  
Deletion Syndrome ◽  
Gene Encoding ◽  
Mitogen Activated Protein ◽  
Craniofacial Features

Congenital heart disease (CHD) occurs in association with extracardiac anomalies or as part of an identified syndrome in 25–40% of cases. Approximately 30% of children with a chromosomal abnormality have CHD. Aneuploidy, or abnormal chromosomal number, accounts for a significant proportion of CHD. Of individuals born with trisomy 21, 50% have CHD, the most common being an atrioventricular septal defect (45%). In segmental aneuploidies, the so-called microdeletion syndromes, small submicroscopic chromosomal deletions can lead to CHD. The 22q11 deletion syndrome causes CHD with thymic and parathyroid hypoplasia (DiGeorge syndrome) and characteristic dysmorphic craniofacial features due to abnormal pharyngeal arch development. Williams–Beuren syndrome with renovascular anomalies, typical elfin facies, and neurological deficits, is characterized by cardiac involvement in the form of supravalvar aortic and peripheral pulmonic stenosis. Chromosome 1p36 deletion syndrome is the most common subterminal deletion syndrome. A substantial proportion of individuals with 1p36 deletion syndrome have CHD which may occur in the presence or absence of cardiomyopathy, most commonly left ventricular non-compaction cardiomyopathy. Single gene mutations may also cause syndromic CHD. Noonan syndrome and related disorders (‘RASopathies’) are caused by dominant gain-of-function mutations in one of the genes which encode proteins that function in the Ras/mitogen-activated protein kinase (RAS-MAPK) signal transduction pathway. Holt–Oram syndrome is associated with mutations in the transcription factor TBX5. Alagille syndrome is caused by mutations in JAG1, a gene encoding a ligand in the Notch signaling pathway. Heterotaxy syndrome, which means randomization of cardiac, pulmonary, or gastrointestinal situs, is frequently associated with CHD.

scholarly journals MerTK signaling in macrophages promotes the synthesis of inflammation resolution mediators by suppressing CaMKII activity

2018 ◽  
Vol 11 (549) ◽  
pp. eaar3721 ◽  
Author(s):  
Bishuang Cai ◽  
Canan Kasikara ◽  
Amanda C. Doran ◽  
Rajasekhar Ramakrishnan ◽  
Raymond B. Birge ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Inflammatory Diseases ◽  
Critical Role ◽  
Mitogen Activated Protein Kinase ◽  
Gene Encoding ◽  
Endoplasmic Reticulum Calcium ◽  
Calcium Calmodulin Dependent ◽  
Mitogen Activated Protein ◽  
Dependent Protein ◽  
Inflammation Resolution

Inflammation resolution counterbalances excessive inflammation and restores tissue homeostasis after injury. Failure of resolution contributes to the pathology of numerous chronic inflammatory diseases. Resolution is mediated by endogenous specialized proresolving mediators (SPMs), which are derived from long-chain fatty acids by lipoxygenase (LOX) enzymes. 5-LOX plays a critical role in the biosynthesis of two classes of SPMs: lipoxins and resolvins. Cytoplasmic localization of the nonphosphorylated form of 5-LOX is essential for SPM biosynthesis, whereas nuclear localization of phosphorylated 5-LOX promotes proinflammatory leukotriene production. We previously showed that MerTK, an efferocytosis receptor on macrophages, promotes SPM biosynthesis by increasing the abundance of nonphosphorylated, cytoplasmic 5-LOX. We now show that activation of MerTK in human macrophages led to ERK-mediated expression of the gene encoding sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (SERCA2), which decreased the cytosolic Ca2+ concentration and suppressed the activity of calcium/calmodulin-dependent protein kinase II (CaMKII). This, in turn, reduced the activities of the mitogen-activated protein kinase (MAPK) p38 and the kinase MK2, resulting in the increased abundance of the nonphosphorylated, cytoplasmic form of 5-LOX and enhanced SPM biosynthesis. In a zymosan-induced peritonitis model, an inflammatory setting in which macrophage MerTK activation promotes resolution, inhibition of ERK activation delayed resolution, which was characterized by an increased number of neutrophils and decreased amounts of SPMs in tissue exudates. These findings contribute to our understanding of how MerTK signaling induces 5-LOX–derived SPM biosynthesis and suggest a therapeutic strategy to boost inflammation resolution in settings where defective resolution promotes disease progression.

scholarly journals The p38 MAPK family, a pushmi-pullyu of skeletal muscle differentiation

2009 ◽  
Vol 187 (7) ◽  
pp. 941-943 ◽  
Author(s):  
Andrew B. Lassar
Keyword(s):  
Skeletal Muscle ◽  
Transcription Factor ◽  
Stem Cell ◽  
Muscle Differentiation ◽  
Mitogen Activated Protein Kinase ◽  
Stem Cell Population ◽  
Skeletal Muscle Differentiation ◽  
Gene Encoding ◽  
Muscle Stem Cell ◽  
Mitogen Activated Protein

In this issue, Gillespie et al. (Gillespie et al. 2009. J. Cell Biol. doi:10.1083/jcb.200907037) demonstrate that the mitogen-activated protein kinase isoform p38-γ plays a crucial role in blocking the premature differentiation of satellite cells, a skeletal muscle stem cell population. p38-γ puts the brakes on skeletal muscle differentiation by promoting the association of the transcription factor MyoD with the histone methyltransferase, KMT1A, which act together in a complex to repress the premature expression of the gene encoding the myogenic transcription factor Myogenin.

scholarly journals Rho1p-Bni1p-Spa2p Interactions: Implication in Localization of Bni1p at the Bud Site and Regulation of the Actin Cytoskeleton inSaccharomyces cerevisiae

1998 ◽  
Vol 9 (5) ◽  
pp. 1221-1233 ◽  
Author(s):  
Takeshi Fujiwara ◽  
Kazuma Tanaka ◽  
Akihisa Mino ◽  
Mitsuhiro Kikyo ◽  
Kazuo Takahashi ◽  
...  
Keyword(s):  
Amino Acid ◽  
Actin Cytoskeleton ◽  
Binding Protein ◽  
Microscopic Analysis ◽  
Mitogen Activated Protein Kinase ◽  
Gene Encoding ◽  
Amino Acid Region ◽  
Genes Encoding ◽  
Mitogen Activated Protein ◽  
Acid Region

Rho1p is a yeast homolog of mammalian RhoA small GTP-binding protein. Rho1p is localized at the growth sites and required for bud formation. We have recently shown that Bni1p is a potential target of Rho1p and that Bni1p regulates reorganization of the actin cytoskeleton through interactions with profilin, an actin monomer-binding protein. Using the yeast two-hybrid screening system, we cloned a gene encoding a protein that interacted with Bni1p. This protein, Spa2p, was known to be localized at the bud tip and to be implicated in the establishment of cell polarity. The C-terminal 254 amino acid region of Spa2p, Spa2p(1213–1466), directly bound to a 162-amino acid region of Bni1p, Bni1p(826–987). Genetic analyses revealed that both thebni1 and spa2 mutations showed synthetic lethal interactions with mutations in the genes encoding components of the Pkc1p-mitogen-activated protein kinase pathway, in which Pkc1p is another target of Rho1p. Immunofluorescence microscopic analysis showed that Bni1p was localized at the bud tip in wild-type cells. However, in the spa2 mutant, Bni1p was not localized at the bud tip and instead localized diffusely in the cytoplasm. A mutant Bni1p, which lacked the Rho1p-binding region, also failed to be localized at the bud tip. These results indicate that both Rho1p and Spa2p are involved in the localization of Bni1p at the growth sites where Rho1p regulates reorganization of the actin cytoskeleton through Bni1p.

scholarly journals HoxA10 Activates Transcription of the Gene Encoding Mitogen-activated Protein Kinase Phosphatase 2 (Mkp2) in Myeloid Cells

2007 ◽  
Vol 282 (22) ◽  
pp. 16164-16176 ◽  
Author(s):  
Hao Wang ◽  
YuFeng Lu ◽  
Weiqi Huang ◽  
E. Terry Papoutsakis ◽  
Peter Fuhrken ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Myeloid Cells ◽  
Mitogen Activated Protein Kinase ◽  
Gene Encoding ◽  
Mitogen Activated Protein

scholarly journals Calcineurin/Crz1 destabilizes Msn2 and Msn4 in the nucleus in response to Ca2+ in Saccharomyces cerevisiae

2010 ◽  
Vol 427 (2) ◽  
pp. 275-287 ◽  
Author(s):  
Yoshifumi Takatsume ◽  
Takumi Ohdate ◽  
Kazuhiro Maeta ◽  
Wataru Nomura ◽  
Shingo Izawa ◽  
...  
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Mitogen Activated Protein Kinase ◽  
Gene Encoding ◽  
Induced Expression ◽  
Glyoxalase 1 ◽  
Cis Element ◽  
Mitogen Activated Protein ◽  
In The Wild ◽  
In Cells

Although methylglyoxal is derived from glycolysis, it has adverse effects on cellular function. Hence, the intrinsic role of methylglyoxal in vivo remains to be determined. Glyoxalase 1 is a pivotal enzyme in the metabolism of methylglyoxal in all types of organisms. To learn about the physiological roles of methylglyoxal, we have screened conditions that alter the expression of the gene encoding glyoxalase 1, GLO1, in Saccharomyces cerevisiae. We show that the expression of GLO1 is induced following treatment with Ca2+ and is dependent on the MAPK (mitogen-activated protein kinase) Hog1 protein and the Msn2/Msn4 transcription factors. Intriguingly, the Ca2+-induced expression of GLO1 was enhanced in the presence of FK506, a potent inhibitor of calcineurin. Consequently, the Ca2+-induced expression of GLO1 in a mutant that is defective in calcineurin or Crz1, the sole transcription factor downstream of calcineurin, was much greater than that in the wild-type strain even without FK506. This phenomenon was dependent upon a cis-element, the STRE (stress-response element), in the promoter that is able to mediate the response to Ca2+ signalling together with Hog1 and Msn2/Msn4. The level of Ca2+-induced expression of GLO1 reached a maximum in cells overexpressing MSN2 even when FK506 was not present, whereas in cells overexpressing CRZ1 the level was greatly reduced and increased markedly when FK506 was present. We also found that the levels of Msn2 and Msn4 proteins in Ca2+-treated cells decreased gradually and that FK506 blocked the degradation of Msn2/Msn4. We propose that Crz1 destabilizes Msn2/Msn4 in the nuclei of cells in response to Ca2+ signalling.

scholarly journals ras2 Controls Morphogenesis, Pheromone Response, and Pathogenicity in the Fungal Pathogen Ustilago maydis

2002 ◽  
Vol 1 (6) ◽  
pp. 954-966 ◽  
Author(s):  
Nancy Lee ◽  
James W. Kronstad
Keyword(s):  
Protein Kinase ◽  
Map Kinase ◽  
Ustilago Maydis ◽  
Mitogen Activated Protein Kinase ◽  
Gene Encoding ◽  
Mitogen Activated Protein ◽  
Kinase Cascade ◽  
Map Kinase Pathway ◽  
Altered Cell ◽  
Kinase Pathway

ABSTRACT Ustilago maydis, a pathogen of maize, is a useful model for the analysis of mating, pathogenicity, and the morphological transition between budding and filamentous growth in fungi. As in other fungi, these processes are regulated by conserved signaling mechanisms, including the cyclic AMP (cAMP)/protein kinase A (PKA) pathway and at least one mitogen-activated protein kinase (MAP kinase) pathway. A current challenge is to identify additional factors that lie downstream of the cAMP pathway and that influence morphogenesis in U. maydis. In this study, we identified suppressor mutations that restored budding growth to a constitutively filamentous mutant with a defect in the gene encoding a catalytic subunit of PKA. Complementation of one suppressor mutation unexpectedly identified the ras2 gene, which is predicted to encode a member of the well-conserved ras family of small GTP-binding proteins. Deletion of the ras2 gene in haploid cells altered cell morphology, eliminated pathogenicity on maize seedlings, and revealed a role in the production of aerial hyphae during mating. We also used an activated ras2 allele to demonstrate that Ras2 promotes pseudohyphal growth via a MAP kinase cascade involving the MAP kinase kinase Fuz7 and the MAP kinase Ubc3. Overall, our results reveal an additional level of crosstalk between the cAMP signaling pathway and a MAP kinase pathway influenced by Ras2.

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