Increased Expression of Serine Palmitoyltransferase (SPT) in Balloon-injured Rat Carotid Artery

2001 ◽  
Vol 86 (11) ◽  
pp. 1320-1326 ◽  
Author(s):  
Jill Carton ◽  
Dennis Argentieri ◽  
Bruce Damiano ◽  
Michael D’Andrea ◽  
David Uhlinger
Keyword(s):  
Vascular Injury ◽  
Potential Role ◽  
De Novo ◽  
Serine Palmitoyltransferase ◽  
Proliferating Cells ◽  
Wound Healing Response ◽  
Complex Wound ◽  
Functional Consequences ◽  
Sphingolipid Biosynthesis

SummaryThe response to vascular injury is a complex wound healing response involving cell proliferation, migration, remodeling and inflammation. In the present studies we employed a rat balloon angioplasty model of vascular injury to investigate the potential role of sphingolipid signaling in the response to vascular injury. The enzyme serine palmitoyltransferase (SPT) catalyzes the first committed step in de novo sphingolipid biosynthesis. We observed marked upregulation of expression of both SPT subunits in actively proliferating cells in injured vessels. This enhanced SPT expression occurs in de-differentiated fibroblasts and proliferating vascular smooth muscle cells. The upregulation is particularly apparent in the proliferating luminal edge of the neointima and the adventitial de-differentiated fibroblasts and may serve as a hallmark of this process. The possible functional consequences of this enzyme upregulation and its role in the response to vascular injury are suggested but remain to be determined.

scholarly journals Viral serine palmitoyltransferase induces metabolic switch in sphingolipid biosynthesis and is required for infection of a marine alga

2016 ◽  
Vol 113 (13) ◽  
pp. E1907-E1916 ◽  
Author(s):  
Carmit Ziv ◽  
Sergey Malitsky ◽  
Alaa Othman ◽  
Shifra Ben-Dor ◽  
Yu Wei ◽  
...  
Keyword(s):  
De Novo ◽  
Serine Palmitoyltransferase ◽  
Metabolic Switch ◽  
Marine Viruses ◽  
Key Enzyme ◽  
Infected Cells ◽  
Biochemical Analyses ◽  
Biological Entities ◽  
Sphingolipid Biosynthesis

Marine viruses are the most abundant biological entities in the oceans shaping community structure and nutrient cycling. The interaction between the bloom-forming algaEmiliania huxleyiand its specific large dsDNA virus (EhV) is a major factor determining the fate of carbon in the ocean, thus serving as a key host-pathogen model system. The EhV genome encodes for a set of genes involved in the de novo sphingolipid biosynthesis, not reported in any viral genome to date. We combined detailed lipidomic and biochemical analyses to characterize the functional role of this virus-encoded pathway during lytic viral infection. We identified a major metabolic shift, mediated by differential substrate specificity of virus-encoded serine palmitoyltransferase, a key enzyme of sphingolipid biosynthesis. Consequently, unique viral glycosphingolipids, composed of unusual hydroxylated C17 sphingoid bases (t17:0) were highly enriched in the infected cells, and their synthesis was found to be essential for viral assembly. These findings uncover the biochemical bases of the virus-induced metabolic rewiring of the host sphingolipid biosynthesis during the chemical “arms race” in the ocean.

Regulation of de novo sphingolipid biosynthesis and the toxic consequences of its disruption

2001 ◽  
Vol 29 (6) ◽  
pp. 831-835 ◽  
Author(s):  
S. C. Linn ◽  
H. S. Kim ◽  
E. M. Keane ◽  
L. M. Andras ◽  
E. Wang ◽  
...  
Keyword(s):  
De Novo ◽  
Uv Light ◽  
Wide Spectrum ◽  
Sphingolipid Metabolism ◽  
Intrinsic Activity ◽  
Type I ◽  
Serine Palmitoyltransferase ◽  
Post Translational Modification ◽  
Sphingolipid Biosynthesis ◽  
Complex Sphingolipids

Complex sphingolipids are ‘built’ on highly bio-active backbones (sphingoid bases and ceramides) that can cause cell death when the amounts are elevated by turnover of complex sphingolipids, disruption of normal sphingolipid metabolism, or over-induction of sphingolipid biosynthesis de novo. Under normal conditions, it appears that the bioactive intermediates of this pathway (3-keto-sphinganine, sphinganine and ceramides) are kept at relatively low levels. Both the intrinsic activity of serine palmitoyltransferase (SPT) and the availability of its substrates (especially palmitoyl-CoA) can have toxic consequences for cells by increasing the production of cytotoxic intermediates. Recent work has also revealed that diverse agonists and stresses (cytokines, UV light, glucocorticoids, heat shock and toxic compounds) modulate SPT activity by induction of SPTLC2 gene transcription and/or post-translational modification. Mutation of the SPTLC1 component of SPT has also been shown to cause hereditary sensory neuropathy type I, possibly via aberrant oversynthesis of sphingolipids. Another key step of the pathway is the acylation of sphinganine (and sphingosine in the recycling pathway) by ceramide synthase, and up-regulation of this enzyme (or its inhibition to cause accumulation of sphinganine) can also be toxic for cells. Since it appears that most, if not all, tissues synthesize sphingolipids de novo, it may not be surprising that disruption of this pathway has been implicated in a wide spectrum of disease.

scholarly journals Crassaostrea gigas Oyster Shell Extract Inhibits Lipogenesis via Suppression of Serine Palmitoyltransferase

2015 ◽  
Vol 10 (2) ◽  
pp. 1934578X1501000
Author(s):  
Nguyen Khoi Song Tran ◽  
Jeong Eun Kwon ◽  
Se Chan Kang ◽  
Soon-Mi Shim ◽  
Tae-Sik Park
Keyword(s):  
De Novo ◽  
Preventive Measure ◽  
Ethanol Extract ◽  
Oyster Shell ◽  
Lipid Lowering ◽  
Metabolic Dysfunction ◽  
Serine Palmitoyltransferase ◽  
Lipogenic Gene Expression ◽  
Cholesterol Levels ◽  
Sphingolipid Biosynthesis

Oysters are widely consumed seafood, but their shells impose a serious environmental problem. To extend the utilization of oyster shell waste, we investigated the biological role of oyster shell extract. In this study, we verified that the ethanol extract of oyster shell (EOS) contains taurine and betaine, the major components of oyster body. EOS downregulated transcription of Sptlc1 and Sptlc2 mRNA, the subunits of serine palmitoyltransferase (SPT). Suppression of SPT subunits reduced sphinganine and sphingomyelin by inhibiting de novo sphingolipid biosynthesis. Inhibition of sphingomyelin biosynthesis resulted in downregulation of lipogenic gene expression such as ACC, FAS, SCD1, and DGAT2. Consistent with inhibition of lipogenesis, cellular triglyceride levels were diminished by EOS, but cholesterol levels were not altered. Taken together, these results suggest that EOS has a lipid-lowering effect and could be applied as either a therapeutic or preventive measure for metabolic dysfunction.

scholarly journals De novo phosphorylation of H2AX by WSTF regulates transcription-coupled homologous recombination repair

2019 ◽  
Vol 47 (12) ◽  
pp. 6299-6314 ◽  
Author(s):  
Jae-Hoon Ji ◽  
Sunwoo Min ◽  
Sunyoung Chae ◽  
Geun-Hyoung Ha ◽  
Yonghyeon Kim ◽  
...  
Keyword(s):  
Homologous Recombination ◽  
Rna Polymerase Ii ◽  
De Novo ◽  
Dna Lesions ◽  
Proliferating Cells ◽  
Histone H2ax ◽  
Rna Transcripts ◽  
Recombination Repair ◽  
Active Transcription

Abstract Histone H2AX undergoes a phosphorylation switch from pTyr142 (H2AX-pY142) to pSer139 (γH2AX) in the DNA damage response (DDR); however, the functional role of H2AX-pY142 remains elusive. Here, we report a new layer of regulation involving transcription-coupled H2AX-pY142 in the DDR. We found that constitutive H2AX-pY142 generated by Williams-Beuren syndrome transcription factor (WSTF) interacts with RNA polymerase II (RNAPII) and is associated with RNAPII-mediated active transcription in proliferating cells. Also, removal of pre-existing H2AX-pY142 by ATM-dependent EYA1/3 phosphatases disrupts this association and requires for transcriptional silencing at transcribed active damage sites. The following recovery of H2AX-pY142 via translocation of WSTF to DNA lesions facilitates transcription-coupled homologous recombination (TC-HR) in the G1 phase, whereby RAD51 loading, but not RPA32, utilizes RNAPII-dependent active RNA transcripts as donor templates. We propose that the WSTF-H2AX-RNAPII axis regulates transcription and TC-HR repair to maintain genome integrity.

scholarly journals Cell-autonomous role of TGFβ and IL-2 receptors in CD4+ and CD8+ inducible regulatory T-cell generation during GVHD

Blood ◽  
2012 ◽  
Vol 119 (23) ◽  
pp. 5575-5583 ◽  
Author(s):  
Norifumi Sawamukai ◽  
Atsushi Satake ◽  
Amanda M. Schmidt ◽  
Ian T. Lamborn ◽  
Priti Ojha ◽  
...  
Keyword(s):  
T Cells ◽  
Potential Role ◽  
Acute Gvhd ◽  
De Novo ◽  
Receptor Expression ◽  
Tgfβ Receptor ◽  
Bona Fide ◽  
Deficient Mice ◽  
Transplantation Recipient

Abstract FoxP3+ regulatory T cells (Tregs) suppress GVHD while preserving graft-versus-tumor effects, making them an attractive target for GVHD therapy. The donor-derived Treg pool can potentially be derived from the expansion of preexisting natural Tregs (nTregs) or from de novo generation of inducible Tregs (iTregs) from donor Tconvs in the transplantation recipient. Using an MHC-mismatched model of acute GVHD, in the present study we found that the Treg pool was comprised equally of donor-derived nTregs and iTregs. Experiments using various combinations of T cells from wild-type and FoxP3-deficient mice suggested that both preexisting donor nTregs and the generation of iTregs in the recipient mice contribute to protection against GVHD. Surprisingly, CD8+FoxP3+ T cells represented approximately 70% of the iTreg pool. These CD8+FoxP3+ T cells shared phenotypic markers with their CD4+ counterparts and displayed suppressive activity, suggesting that they were bona fide iTregs. Both CD4+ and CD8+ Tregs appeared to be protective against GVHD-induced lethality and required IL-2 and TGFβ receptor expression for their generation. These data illustrate the complex makeup of the donor-derived FoxP3+ Treg pool in allogeneic recipients and their potential role in protection against GVHD.

Abstract P212: Sphingolipid De Novo Pathway is a Novel Regulator of Blood Pressure Homeostasis

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Anna Cantalupo ◽  
Yi Zhang ◽  
Xian-Cheng Jiang ◽  
Annarita Di Lorenzo
Keyword(s):  
Blood Pressure ◽  
Endothelial Cells ◽  
High Blood Pressure ◽  
Vascular Reactivity ◽  
De Novo ◽  
Ex Vivo ◽  
Mesenteric Arteries ◽  
Serine Palmitoyltransferase ◽  
Sphingosine 1 Phosphate

Background and objectives: Sphingolipids, particularly sphingosine 1-phosphate (S1P), play an important role in the cardiovascular homeostasis. Recently, we revealed that endothelial de novo biosynthesis of sphingolipids is very important to control vascular functions and blood pressure. We discovered that in blood vessels, particularly in endothelial cells, Nogo-B, a membrane protein of the endoplasmic reticulum, inhibits serine palmitoyltransferase (SPT), the first and rate-limiting enzyme of de novo production of sphingolipids, to impact vascular tone and blood pressure. Indeed, mice lacking Nogo-B are protected from angiotensin II-induced hypertension, and pharmacological inhibition of SPT by myriocin reinstates high blood pressure in absence of Nogo-B, suggesting that the upregulation of SPT activity exerts anti-hypertensive functions. Thus, the goal of this study is to investigate the role of SPT in vascular functions and blood pressure regulation by using novel genetic mouse models. Methods: The SBP was evaluated in 14 weeks old mice heterozygous for Sptlc2 ( Sptlc2 +/- ) or lacking Sptlc2 specifically in endothelial cells (ECKO Sptlc2 ) and smooth muscle cells (SMCKO Sptlc2 ) by using tail-cuff system. Vascular reactivity of isolated mesenteric arteries was assessed ex-vivo by using the pressure myograph system. Results: Sptlc2 +/- , ECKO Sptlc2 and SMCKO Sptlc2 mice were hypertensive compared to their respective controls ( Sptlc2 +/- 128.9±2.6 vs. WT 112.1±2.6 mmHg; ECKO Sptlc2 125.5±1.8, SMCKO Sptlc2 127.2±0.6 vs. Sptlc2 f/f 106±0.84 mmHg) and developed endothelial dysfunction as shown by the impaired vasodilation in response to acetylcholine (EC 50 Sptlc2 +/- 1.48x10 -6 M vs. WT 4.46x10 -7 M; Emax ECKO Sptlc2 73.2±3.3% vs. Sptlc2 f/f 95.3±1.1%), as well as to flow (Emax: Sptlc2 +/- 23.3±1.4 μm vs. WT 42.9±4.4 μm; ECKO Sptlc2 19.9±0.9 μm vs. Sptlc2 f/f 41.3±3.1 μm). Conclusion: This study demonstrates the important role of SPT, thus the de novo production of sphingolipids, in controlling blood flow and pressure homeostasis, and provides the ground for the development of alternative therapeutic strategies to manage high blood pressure.

scholarly journals Chromosomal rearrangements in the 11p15 imprinted region: 17 new 11p15.5 duplications with associated phenotypes and putative functional consequences

2017 ◽  
Vol 55 (3) ◽  
pp. 205-213 ◽  
Author(s):  
Solveig Heide ◽  
Sandra Chantot-Bastaraud ◽  
Boris Keren ◽  
Madeleine D Harbison ◽  
Salah Azzi ◽  
...  
Keyword(s):  
De Novo ◽  
Chromosomal Rearrangements ◽  
Paternal Allele ◽  
Parental Origin ◽  
Imprinted Genes ◽  
Phenotype Correlation ◽  
Growth Disturbance ◽  
Correlation Studies ◽  
Functional Consequences

BackgroundThe 11p15 region contains two clusters of imprinted genes. Opposite genetic and epigenetic anomalies of this region result in two distinct growth disturbance syndromes: Beckwith-Wiedemann (BWS) and Silver-Russell syndromes (SRS). Cytogenetic rearrangements within this region represent less than 3% of SRS and BWS cases. Among these, 11p15 duplications were infrequently reported and interpretation of their pathogenic effects is complex.ObjectivesTo report cytogenetic and methylation analyses in a cohort of patients with SRS/BWS carrying 11p15 duplications and establish genotype/phenotype correlations.MethodsFrom a cohort of patients with SRS/BWS with an abnormal methylation profile (using ASMM-RTQ-PCR), we used SNP-arrays to identify and map the 11p15 duplications. We report 19 new patients with SRS (n=9) and BWS (n=10) carrying de novo or familial 11p15 duplications, which completely or partially span either both telomeric and centromeric domains or only one domain.ResultsLarge duplications involving one complete domain or both domains are associated with either SRS or BWS, depending on the parental origin of the duplication. Genotype-phenotype correlation studies of partial duplications within the telomeric domain demonstrate the prominent role of IGF2, rather than H19, in the control of growth. Furthermore, it highlights the role of CDKN1C within the centromeric domain and suggests that the expected overexpression of KCNQ1OT1 from the paternal allele (in partial paternal duplications, excluding CDKN1C) does not affect the expression of CDKN1C.ConclusionsThe phenotype associated with 11p15 duplications depends on the size, genetic content, parental inheritance and imprinting status. Identification of these rare duplications is crucial for genetic counselling.

scholarly journals Serine and one-carbon metabolisms bring new therapeutic venues in prostate cancer

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Carlo Ganini ◽  
Ivano Amelio ◽  
Riccardo Bertolo ◽  
Eleonora Candi ◽  
Angela Cappello ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Carbon Metabolism ◽  
Potential Role ◽  
De Novo ◽  
Cancer Pathogenesis ◽  
Gene And Protein Expression ◽  
Serine Pathway ◽  
One Carbon Metabolism ◽  
Serine Metabolism

AbstractSerine and one-carbon unit metabolisms are essential biochemical pathways implicated in fundamental cellular functions such as proliferation, biosynthesis of important anabolic precursors and in general for the availability of methyl groups. These two distinct but interacting pathways are now becoming crucial in cancer, the de novo cytosolic serine pathway and the mitochondrial one-carbon metabolism. Apart from their role in physiological conditions, such as epithelial proliferation, the serine metabolism alterations are associated to several highly neoplastic proliferative pathologies. Accordingly, prostate cancer shows a deep rearrangement of its metabolism, driven by the dependency from the androgenic stimulus. Several new experimental evidence describes the role of a few of the enzymes involved in the serine metabolism in prostate cancer pathogenesis. The aim of this study is to analyze gene and protein expression data publicly available from large cancer specimens dataset, in order to further dissect the potential role of the abovementioned metabolism in the complex reshaping of the anabolic environment in this kind of neoplasm. The data suggest a potential role as biomarkers as well as in cancer therapy for the genes (and enzymes) belonging to the one-carbon metabolism in the context of prostatic cancer.

Potential Role of Recombinant Annexin II in Diabetic Vascular Injury

2006 ◽  
Vol 947 (1) ◽  
pp. 308-311 ◽  
Author(s):  
HIDETO ISHII ◽  
MASAYUKI YOSHIDA ◽  
KATHERINE A. HAJJAR ◽  
AKIRA TANAKA ◽  
YUKIO YASUKOCHI ◽  
...  
Keyword(s):  
Vascular Injury ◽  
Potential Role ◽  
Annexin Ii

Evidence for cAMP as a mediator of gonadotropin secretion from male pituitaries

1987 ◽  
Vol 253 (3) ◽  
pp. E296-E299
Author(s):  
G. A. Bourne ◽  
D. M. Baldwin
Keyword(s):  
Protein Synthesis ◽  
Potential Role ◽  
De Novo ◽  
Follicle Stimulating Hormone ◽  
Gonadotropin Releasing Hormone ◽  
Dibutyryl Camp ◽  
Camp Production ◽  
Gonadotropin Secretion ◽  
De Novo Protein Synthesis

The purpose of this study was to use sodium flufenamate, a compound that inhibits gonadotropin-releasing hormone (GnRH)-stimulated adenosine 3',5'-cyclic monophosphate (cAMP) production in the pituitary, to evaluate the potential role of cAMP as a mediator of GnRH-stimulated gonadotropin secretion from male pituitaries. Quartered male pituitaries were perifused at 37 degrees C and sequential effluent fractions collected every 10 min. Infusions of GnRH resulted in a twofold increase in luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion. Cycloheximide, 5 microM, completely inhibited the GnRH-stimulated LH and FSH secretion. Infusions of 0.1 mM flufenamate had similar effects on gonadotropin secretion as cycloheximide, whereas the administration of 5 mM dibutyryl cAMP in combination with GnRH and flufenamate restored the secretory responses of both hormones. The flufenamate-inhibited GnRH stimulated LH and FSH release, which was restored by DBcAMP and appeared to be protein synthesis dependent and specific for cAMP. These results suggest an indirect role for cAMP as a mediator of gonadotropin secretion from male pituitaries. However, in contrast to female pituitaries, the secretion of these hormones from male pituitaries is completely dependent on cAMP and de novo protein synthesis.

Sign in / Sign up

Export Citation Format

Share Document