bims-polyam Biomed news
on Polyamines
Issue of 2019‒04‒14
six papers selected by
Alexander Ivanov
Engelhardt Institute of Molecular Biology

  1. Amino Acids. 2019 Apr 10.
    Stump CL, Feehan RP, Jordan T, Shantz LM, Nowotarski SL.
      Non-melanoma skin cancer (NMSC) is the most common form of cancer. Ultraviolet-B (UVB) radiation has been shown to be a complete carcinogen in the development of NMSC. The mammalian target of rapamycin complex 1 (mTORC1) is upregulated by UVB. Ornithine decarboxylase (ODC), the first enzyme of the polyamine biosynthetic pathway, is also upregulated in response to UVB. However, the interplay between these two pathways after UVB exposure remains unclear. The studies described here compare mRNA stability between normal human keratinocytes (HaCaT cells) and HaCaT cells with low levels of raptor to investigate whether the induction of ODC by UVB is dependent on mTORC1. We show that the knockdown of mTORC1 activity led to decreased levels of ODC protein both before and after exposure to 20 mJ/cm2 UVB. ODC mRNA was less stable in cells with decreased mTORC1 activity. Polysome profiles revealed that the initiation of ODC mRNA translation did not change in UVB-treated cells. We have shown that the ODC transcript is stabilized by the RNA-binding protein human antigen R (HuR). To expand these studies, we investigated whether HuR functions to regulate ODC mRNA stability in human keratinocytes exposed to UVB. We show an increased cytoplasmic localization of HuR after UVB exposure in wild-type cells. The ablation of HuR via CRISPR/Cas9 did not alter the stability of the ODC message, suggesting the involvement of other trans-acting factors. These data suggest that in human keratinocytes, ODC mRNA stability is regulated, in part, by an mTORC1-dependent mechanism after UVB exposure.
    Keywords:  Ornithine decarboxylase; Post-transcriptional regulation; mRNA stability; mTOR
  2. Molecules. 2019 Apr 09. pii: E1395. [Epub ahead of print]24(7):
    Fu Y, Gu Q, Dong Q, Zhang Z, Lin C, Hu W, Pan R, Guan Y, Hu J.
      Polyamines have been reported to be involved in grain filling and they might contribute to the construction of heat resistance of some cereals. In this study, the hybrid rice 'YLY 689' was used to explore the possible effects of exogenous spermidine (Spd) on seed quality under high temperature during the filling stage. Rice spikes were treated with Spd or its synthesis inhibitor cyclohexylamine (CHA) after pollination, and then the rice plants were transferred to 40 °C for 5-day heat treatment. The results showed that, compared with the control under high temperature, Spd pretreatment significantly improved the germination percentage, germination index, vigor index, seedling shoot height, and dry weight of seeds harvested at 35 days after pollination, while the CHA significantly decreased the seed germination and seedling growth. Meanwhile, Spd significantly increased the peroxidase (POD) activity and decreased the malondialdehyde (MDA) content in seeds. In addition, after spraying with Spd, the endogenous content of spermidine and spermine and the expression of their synthetic genes, spermidine synthase (SPDSYN) and spermine synthase (SPMS1 and SPMS2), significantly increased, whereas the accumulation of amylose and total starch and the expression of their related synthase genes, soluble starch synthase II-3 (SS II-3) and granules bound starch synthase I (GBSSI), also increased to some extent. The data suggests that exogenous Spd pretreatment could alleviate the negative impacts of high temperature stress on rice seed grain filling and improve the rice seed quality to some extent, which might be partly caused by up-regulating endogenous polyamines and starch metabolism.
    Keywords:  grain filling; high temperature; polyamines; spermidine; starch
  3. Biosci Rep. 2019 Apr 09. pii: BSR20190326. [Epub ahead of print]
    Timson DJ.
      A recent paper in Bioscience Reports (BSR20182189) describes the discovery of an interaction between the motor protein myosin Va and the metabolic enzyme spermine synthase.  Myosin Va is a molecular motor which plays a key role in vesicle transport.  Mutations in the gene which encodes this protein are associated with Griscelli syndrome type 1 and the "dilute" phenotype in animals.  Spermine synthase catalyses the conversion of spermidine to spermine.  This largely cytoplasmic enzyme can also be localised to the soluble fraction in exosomes.  Mutations in the spermine synthase gene are associated with Snyder Robinson mental retardation syndrome.  The interaction between the two proteins was detected using the yeast two hybrid method and verified by microscale thermophoresis of recombinant proteins.  Knockdown of the MYO5A gene reduced the expression of mRNA coding for spermine synthase.  The amount of this transcript was also reduced in cells derived from a patient with Griscelli syndrome type 1.  This suggests that, in addition to a direct physical interaction between the two proteins, myosin Va also modulates the transcription of the spermine synthase gene.  The mechanism for this modulation is currently unknown.  These findings have implications for Griscelli syndrome type 1 and Snyder Robinson mental retardation syndrome.  They also suggest that interactions between myosin Va and soluble exosome proteins such as spermine synthase may be important in the mechanism of exosome transport.
    Keywords:  Griscelli syndrome; Snyder Robinson mental retardation syndrome; cytoskeleton; exosome transport; myosin superfamily; polyamine synthesis
  4. Front Cell Infect Microbiol. 2019 ;9 66
    Singh K, Gobert AP, Coburn LA, Barry DP, Allaman M, Asim M, Luis PB, Schneider C, Milne GL, Boone HH, Shilts MH, Washington MK, Das SR, Piazuelo MB, Wilson KT.
      There is great interest in safe and effective alternative therapies that could benefit patients with inflammatory bowel diseases (IBD). L-arginine (Arg) is a semi-essential amino acid with a variety of physiological effects. In this context, our aim was to investigate the role of dietary Arg in experimental colitis. We used two models of colitis in C57BL/6 mice, the dextran sulfate sodium (DSS) model of injury and repair, and Citrobacter rodentium infection. Animals were given diets containing (1) no Arg (Arg0), 6.4 g/kg (ArgNL), or 24.6 g/kg Arg (ArgHIGH); or (2) the amino acids downstream of Arg: 28 g/kg L-ornithine (OrnHIGH) or 72 g/kg L-proline (ProHIGH). Mice with DSS colitis receiving the ArgHIGH diet had increased levels of Arg, Orn, and Pro in the colon and improved body weight loss, colon length shortening, and histological injury compared to ArgNL and Arg0 diets. Histology was improved in the ArgNL vs. Arg0 group. OrnHIGH or ProHIGH diets did not provide protection. Reduction in colitis with ArgHIGH diet also occurred in C. rodentium-infected mice. Diversity of the intestinal microbiota was significantly enhanced in mice on the ArgHIGH diet compared to the ArgNL or Arg0 diets, with increased abundance of Bacteroidetes and decreased Verrucomicrobia. In conclusion, dietary supplementation of Arg is protective in colitis models. This may occur by restoring overall microbial diversity and Bacteroidetes prevalence. Our data provide a rationale for Arg as an adjunctive therapy in IBD.
    Keywords:  alternative therapies; arginine; experimental colitis; gut microbiota; inflammatory bowel diseases
  5. J Food Sci. 2019 Apr;84(4): 717-725
    Hu C, Zhang Y, Liu G, Liu Y, Wang J, Sun B.
      The study aimed to explore the metabolic changes of adipose tissue of hyperlipidemia rats with hawthorn ethanol extracts (HEE) consumption by a high-throughput metabolomics approach. HEE were mainly composed of chlorogenic acid, hyperoside, isoquercitrin, rutin, vitexin, quercetin, and apigenin by HPLC analysis. HEE administration significantly lowered levels of the total cholesterols, triglyceride and low-density lipoprotein cholesterol as compared to the high-fat diet model. Gas chromatography-mass spectrometry was used to identify adipose metabolite profiles. Numerous endogenous molecules were altered by high-fat diet and restored following intervention of HEE. Metabolites elevated in adipose, including l-threonine, aspartic acid, glutamine, mannose, inositol and oleic acid, were detected after HEE consumption. Fifteen metabolites were identified as potential biomarkers of hyperlipidemia. Pathway analysis showed that most of the discriminant metabolites were included in fatty acid biosynthesis, galactose metabolism, biosynthesis of unsaturated fatty acids, arginine and proline metabolism, alanine, aspartate and glutamate metabolism, glycerolipid metabolism and steroid biosynthesis. These metabolites and metabolic networks we found offer new insights into exploring the molecular mechanisms of lipid-lowering of hawthorn ethanol extracts on adipose tissue of rats. PRACTICAL APPLICATION: There was a very high proportion of hyperlipidemia in China. Hawthorn is attracting increasing attention owing to their health benefits, low toxicity, effectiveness and might be suitable for long-term use.
    Keywords:  GC-MS; adipose tissue; hawthorn; metabolomics; untargeted metabolite profiling
  6. Cell Metab. 2019 Apr 01. pii: S1550-4131(19)30133-0. [Epub ahead of print]
    Jung JW, Macalino SJY, Cui M, Kim JE, Kim HJ, Song DG, Nam SH, Kim S, Choi S, Lee JW.
      The mechanistic target of rapamycin complex (mTORC1) is a signaling hub on the lysosome surface, responding to lysosomal amino acids. Although arginine is metabolically important, the physiological arginine sensor that activates mTOR remains unclear. Here, we show that transmembrane 4 L six family member 5 (TM4SF5) translocates from plasma membrane to lysosome upon arginine sufficiency and senses arginine, culminating in mTORC1/S6K1 activation. TM4SF5 bound active mTOR upon arginine sufficiency and constitutively bound amino acid transporter SLC38A9. TM4SF5 binding to the cytosolic arginine sensor Castor1 decreased upon arginine sufficiency, thus allowing TM4SF5-mediated sensing of metabolic amino acids. TM4SF5 directly bound free L-arginine via its extracellular loop possibly for the efflux, being supported by mutant study and homology and molecular docking modeling. Therefore, we propose that lysosomal TM4SF5 senses and enables arginine efflux for mTORC1/S6K1 activation, and arginine-auxotroph in hepatocellular carcinoma may be targeted by blocking the arginine sensing using anti-TM4SF5 reagents.
    Keywords:  TM4SF5; amino acid transporter; arginine sensor; homology modeling; lysosome; mTOR; metabolism; molecular docking modeling; protein interaction; tetraspanin trafficking