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Glycine regulates proliferation and differentiation of salivary-gland-derived progenitor cells

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Abstract

Amino acids have various physiological activities that influence processes such as intestinal regeneration, EGF secretion, protein synthesis, and cell growth. Salivary glands are exposed to nutrients that influence their proliferation and regeneration. Glycine is included in saliva in large quantities and reportedly has important roles in antibacterial activities and the inhibition of tumor growth and as a precursor of nucleotide synthesis in cell proliferation. We have investigated the effects of glycine on the proliferation and differentiation of salivary glands by using mouse salivary-gland-derived progenitor (mSGP) cells. In cultures of mSGP cells, cell proliferation is suppressed in the presence of glycine, whereas it is promoted by its removal. Glycine promotes three-dimensional formations of mSGP cells, which are negative for immature markers and positive for differentiation markers. In cell-cycle analysis, cell-cycle progression is delayed at the S-phase by glycine supplementation. Glycine also suppresses the phosphorylation of p42/p44MAPK. These results suggest that glycine suppresses the proliferation and promotes the differentiation of mSGP cells, and that it has inhibitory effects on growth factor signaling and cell-cycle progression. Glycine might therefore be a physiological activator that regulates the proliferation and differentiation of salivary glands.

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References

  • Amano A, Fujiwara T, Nagata H, Kuboniwa M, Sharma A, Sojar HT, Genco RJ, Hamada S, Shizukuishi S (1997) Prophyromonas gingivalis fimbriae mediate coaggregation with Streptococcus oralis through specific domains. J Dent Res 76:852–857

    Article  PubMed  CAS  Google Scholar 

  • Cardoso WV, Lu J (2006) Regulation of early lung morphogenesis: questions, facts and controversies. Development 133:1611–1624

    Article  PubMed  CAS  Google Scholar 

  • Dangi S, Chen FM, Shapiro P (2006) Activation of extracellular signal-regulated kinase (ERK) in G2 phase delays mitotic entry through p21CIP1. Cell Prolif 39:261–279

    Article  PubMed  CAS  Google Scholar 

  • Delia D, Goi K, Mizutani S, Yamada T, Aiello A, Fontanella E, Lamorte G, Iwata S, Ishioka C, Krajewski S, et al (1997) Dissociation between cell cycle arrest and apoptosis can occur in Li-Fraumeni cells heterozygous for p53 gene mutations. Oncogene 14:2137–2147

    Article  PubMed  CAS  Google Scholar 

  • Denny PC, Ball WD, Redman RS (1997) Salivary glands: a paradigm for diversity of gland development. Crit Rev Oral Biol Med 8:51–75

    Article  PubMed  CAS  Google Scholar 

  • Drucker DJ, Erlich P, Asa SL, Brubaker PL (1996) Induction of intestinal epithelial proliferation by glucagon-like peptide 2. Proc Natl Acad Sci USA 93:7911–7916

    Article  PubMed  CAS  Google Scholar 

  • Gentile M, Latonen L, Laiho M (2003) Cell cycle arrest and apoptosis provoked by UV radiation-induced DNA damage are transcriptionally highly divergent responses. Nucleic Acids Res 31:4779–4790

    Article  PubMed  CAS  Google Scholar 

  • Ghavanini AA, Mathers DA, Puil E (2005) Glycinergic inhibition in thalamus revealed by synaptic receptor blockade. Neuropharmacology 49:338–349

    Article  PubMed  CAS  Google Scholar 

  • Ghigo E, Bartolotta E, Imperiale E, Bellone J, Cardinale G, Aimaretti G, Valetto MR, Cherubini V, Maccario M, Cocchi D, et al (1994) Glucagon stimulates GH secretion after intramuscular but not intravenous administration. Evidence against the assumption that glucagon per se has a GH-releasing activity. J Endocrinol Invest 17:849–854

    PubMed  CAS  Google Scholar 

  • Goldberg AL, Chang TW (1978) Regulation and significance of amino acid metabolism in skeletal muscle. Fed Proc 37:2301–2307

    PubMed  CAS  Google Scholar 

  • Harper AE, Miller RH, Block KP (1984) Branched-chain amino acid metabolism. Annu Rev Nutr 4:409–454

    Article  PubMed  CAS  Google Scholar 

  • Hisatomi Y, Okumura K, Nakamura K, Matsumoto S, Satoh A, Nagano K, Yamamoto T, Endo F (2004) Flow cytometric isolation of endodermal progenitors from mouse salivary gland differentiate into hepatic and pancreatic lineages. Hepatology 39:667–675

    Article  PubMed  Google Scholar 

  • Ichinohe A, Kure S, Mikawa S, Ueki T, Kojima K, Fujiwara K, Iinuma K, Matsubara Y, Sato K (2004) Glycine cleavage system in neurogenic regions. Eur J Neurosci 19:2365–2370

    Article  PubMed  Google Scholar 

  • Jones SM, Kazlauskas A (2001) Growth factor-dependent signaling and cell cycle progression. Chem Rev 101:2413–2423

    Article  PubMed  CAS  Google Scholar 

  • Larsen WJ (2001) Human embryology, 3rd edn. Churchill Livingstone, Edinburgh

    Google Scholar 

  • Larsen M, Hoffman MP, Sakai T, Neibaur JC, Mitchell JM, Yamada KM (2003) Role of PI 3-kinase and PIP3 in submandibular gland branching morphogenesis. Dev Biol 255:178–191

    Article  PubMed  CAS  Google Scholar 

  • Lianguzova MS, Chuykin IA, Nordheim A, Pospelov VA (2007) Phosphoinositide 3-kinase inhibitor LY294002 but not serum withdrawal suppresses proliferation of murine embryonic stem cells. Cell Biol Int 31:330–337

    Article  PubMed  CAS  Google Scholar 

  • Lieberthal W, Triaca V, Koh JS, Pagano PJ, Levine JS (1998) Role of superoxide in apoptosis induced by growth factor withdrawal. Am J Physiol 275:F691–F702

    PubMed  CAS  Google Scholar 

  • Liu Y, Martinez L, Ebine K, Abe MK (2008) Role for mitogen-activated protein kinase p38 alpha in lung epithelial branching morphogenesis. Dev Biol 314:224–235

    Article  PubMed  CAS  Google Scholar 

  • Liu Y, Wong TP, Aarts M, Rooyakkers A, Liu L, Lai TW, Wu DC, Lu J, Tymianski M, Craig AM, et al (2007) NMDA receptor subunits have differential roles in mediating excitotoxic neuronal death both in vitro and in vivo. J Neurosci 27:2846–2857

    Article  PubMed  CAS  Google Scholar 

  • Maezono K, Mawatari K, Kajiwara K, Shinkai A, Maki T (1996) Effect of alanine on D-galactosamine-induced acute liver failure in rats. Hepatology 24:1211–1216

    PubMed  CAS  Google Scholar 

  • Matsumoto S, Okumura K, Ogata A, Hisatomi Y, Sato A, Hattori K, Matsumoto M, Kaji Y, Takahashi M, Yamamoto T, et al (2007) Isolation of tissue progenitor cells from duct-ligated salivary glands of swine. Cloning Stem Cells 9:176–190

    Article  PubMed  CAS  Google Scholar 

  • Meloche S, Pouyssegur J (2007) The ERK1/2 mitogen-activated protein kinase pathway as a master regulator of the G1- to S-phase transition. Oncogene 26:3227–3239

    Article  PubMed  CAS  Google Scholar 

  • Nam HJ, Kim S, Lee MW, Lee BS, Hara T, Saya H, Cho H, Lee JH (2008) The ERK-RSK1 activation by growth factors at G2 phase delays cell cycle progression and reduces mitotic aberrations. Cell Signal 20:1349–1358

    Article  PubMed  CAS  Google Scholar 

  • Okumura K, Nakamura K, Hisatomi Y, Nagano K, Tanaka Y, Terada K, Sugiyama T, Umeyama K, Matsumoto K, Yamamoto T, Endo E (2003) Salivary gland progenitor cells induced by duct ligation differentiate into hepatic and pancreatic lineages. Hepatology 38:104–113

    Article  PubMed  Google Scholar 

  • Pardee AB (1974) A restriction point for control of normal animal cell proliferation. Proc Natl Acad Sci USA 71:1286–1290

    Article  PubMed  CAS  Google Scholar 

  • Pardee AB (1989) G1 events and regulation of cell proliferation. Science 246:603–608

    Article  PubMed  CAS  Google Scholar 

  • Peranzoni E, Marigo I, Dolcetti L, Ugel S, Sonda N, Taschin E, Mantelli B, Bronte V, Zanovello P (2007) Role of arginine metabolism in immunity and immunopathology. Immunobiology 212:795–812

    Article  PubMed  CAS  Google Scholar 

  • Rees DD, Monkhouse JE, Cambridge D, Moncada S (1998) Nitric oxide and the haemodynamic profile of endotoxin shock in the conscious mouse. Br J Pharmacol 124:540–546

    Article  PubMed  CAS  Google Scholar 

  • Reynolds JV, Daly JM, Shou J, Sigal R, Ziegler MM, Naji A (1990) Immunologic effects of arginine supplementation in tumor-bearing and non-tumor-bearing hosts. Ann Surg 211:202–210

    Article  PubMed  CAS  Google Scholar 

  • Rose ML, Cattley RC, Dunn C, Wong V, Li X, Thurman RG (1999a) Dietary glycine prevents the development of liver tumors caused by the peroxisome proliferator WY-14,643. Carcinogenesis 20:2075–2081

    Article  PubMed  CAS  Google Scholar 

  • Rose ML, Madren J, Bunzendahl H, Thurman RG (1999b) Dietary glycine inhibits the growth of B16 melanoma tumors in mice. Carcinogenesis 20:793–798

    Article  PubMed  CAS  Google Scholar 

  • Sakata Y, Owada Y, Sato K, Kojima K, Hisanaga K, Shinka T, Suzuki Y, Aoki Y, Satoh J, Kondo H, et al (2001) Structure and expression of the glycine cleavage system in rat central nervous system. Brain Res Mol Brain Res 94:119–130

    Article  PubMed  CAS  Google Scholar 

  • Sato A, Okumura K, Matsumoto S, Hattori K, Hattori S, Shinohara M, Endo F (2007) Isolation, tissue localization, and cellular characterization of progenitors derived from adult human salivary glands. Cloning Stem Cells 9:191–205

    Article  PubMed  CAS  Google Scholar 

  • Shackelford RE, Kaufmann WK, Paules RS (1999) Cell cycle control, checkpoint mechanisms, and genotoxic stress. Environ Health Perspect 107 (Suppl 1):5–24

    Article  PubMed  CAS  Google Scholar 

  • Wheatley DN, Scott L, Lamb J, Smith S (2000) Single amino acid (arginine) restriction: growth and death of cultured HeLa and human diploid fibroblasts. Cell Physiol Biochem 10:37–55

    Article  PubMed  CAS  Google Scholar 

  • Wilmore DW, Smith RJ, O’Dwyer ST, Jacobs DO, Ziegler TR, Wang XD (1988) The gut: a central organ after surgical stress. Surgery 104:917–923

    PubMed  CAS  Google Scholar 

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Acknowledgment

We thank AJINOMOTO for assistance with the supply of δ media and amino-acid-free medium, Yuichirou Hisatomi for assistance with the supply of mouse SGP cells, Tatsuko Kubo for assistance with the preparation of tissue for histology, and Kaede Yanagida and Dr. Kevin Boru for assistance with writing the manuscript.

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Authors and Affiliations

  1. Department of Pediatrics, Kumamoto University, Graduate School of Medical Sciences, Kumamoto City, Japan

    Yasuko Nakamura, Taiga Mochida & Fumio Endo

  2. Department of Pediatrics, Kumamoto University School of Medicine, 1–1–1, Honjo, Kumamoto City, 860–8556, Japan

    Shirou Matsumoto, Kimitoshi Nakamura & Fumio Endo

  3. Pharmaceutical Research Laboratories, AJINOMOTO, Kawasaki, Japan

    Kenji Takehana

Authors
  1. Yasuko Nakamura
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  2. Shirou Matsumoto
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  3. Taiga Mochida
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  4. Kimitoshi Nakamura
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  5. Kenji Takehana
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  6. Fumio Endo
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Corresponding author

Correspondence to Fumio Endo.

Additional information

This work was supported in part by the Advanced Education Program for Integrated Clinical, Basic and Social Medicine, Graduate School of Medical Sciences, Kumamoto University (Support Program for Improving Graduate School Education, MEXT,　Japan).

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Supplementary Fig. 1

Apoptosis analysis by flow cytometry. The number of cleaved-caspase positive cells and propidium ionide (PI) positive cells was determined by flow cytometry after treatment of mSGP cells with glycine. (a) PI positive cells (b) Cleaved-caspase positive cells. The number of both the cleaved-caspase positive cells and PI positive cells remained unaffected in either the presence or absence of glycine. (GIF 48.0 KB)

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Nakamura, Y., Matsumoto, S., Mochida, T. et al. Glycine regulates proliferation and differentiation of salivary-gland-derived progenitor cells. Cell Tissue Res 336, 203–212 (2009). https://doi.org/10.1007/s00441-009-0767-0

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  • DOI: https://doi.org/10.1007/s00441-009-0767-0

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