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PTH regulation of c-Jun terminal kinase and p38 MAPK cascades in intestinal cells from young and aged rats

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Abstract

In the present study, we examined the role of Parathyroid hormone (PTH) on the c-Jun N-terminal kinase (JNK) 1/2 and p38 mitogen-activated protein kinase (MAPK) members of the MAPK family as it relates to ageing by measuring hormone-induced changes in their activity in enterocytes isolated from young (3 month old) and aged (24 month old) rats. Our results show that PTH induces a transient activation of JNK 1/2, peaking at 1 min (+threefold). The hormone also stimulates JNK 1/2 tyrosine phosphorylation, in a dose-dependent fashion, this effect being maximal at 10 nM. PTH-induced JNK 1/2 phosphorylation was suppressed by its selective inhibitor SP600125. Moreover, hormone-dependent activation of JNK 1/2 was dependent on calcium, since pretreatment of cells with BAPTA-AM or EGTA blocked PTH effects. With ageing, the response to PTH was significantly reduced. JNK basal protein expression was not different in the enterocytes from young and aged rats, however, basal protein phosphorylation increased with ageing. PTH did not stimulate, within 1–10 min, the basal activity and phosphorylation of p38 MAPK in rat intestinal cells. The hormone increased enterocyte DNA synthesis; the response was dose-dependent and decreased (-40%) with ageing. In agreement with the mitogenic role of the MAPK cascades, this effect was blocked by specific inhibitors of extracellular signal-regulated protein kinase (ERK) 1/2 and JNK 1/2. The results obtained in this work expand our knowledge on the mechanism of action of PTH in duodenal cells.

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References

  • Abou-Samra AB, Jueppner H, Westerberg D, Potts JT Jr, Segre GV (1989) Parathyroid hormone causes translocation of protein kinase C from cytosol to membranes in rat osteosarcoma cells. Endocrinology 124:1107–1113

    Article  PubMed  CAS  Google Scholar 

  • Banerjee S, Narayanan K, Mizutani T, Makino S (2002) Murine coronavirus replication-induced p38 mitogen-activated protein kinase activation promotes interleukin-6 production and virus replication in cultured cells. J Virol 76:5937–5948

    Article  PubMed  CAS  Google Scholar 

  • Bennett BL, Sasaki DT, Murray BW, O’Leary EC, Sakata ST, Xu W, Leisten JC, Motiwala A, Pierce S, Satoh Y, Bhagwat SS, Manning AM, Anderson DW (2001) SP600125, an anthrapyrazolone inhibitor of Jun N-terminal kinase. Proc Natl Acad Sci USA 98:13681–13686

    Article  PubMed  CAS  Google Scholar 

  • Bradford M (1976) A rapid and sensitive method for the quantification of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–254

    Article  PubMed  CAS  Google Scholar 

  • Chan AS, Wong YH (2004) Gbetagamma signaling and Ca2+ mobilization co-operate synergistically in a Sos- and Rac-dependent manner in the activation of JNK by Gq-coupled receptors. Cell Signal 16:823–836

    Article  PubMed  CAS  Google Scholar 

  • Chang L, Karin M (2001) Mammalian MAP kinase signaling cascades. Nature 410:37–40

    Article  PubMed  CAS  Google Scholar 

  • Chen G, Hitomi M, Han J, Stacey DW (2000) The p38 pathway provides negative feedback for Ras proliferative signaling. J Biol Chem 275:38973–38980

    Article  PubMed  CAS  Google Scholar 

  • Cobb MH, Goldsmith EJ (1995) How MAP kinases are regulated. J Biol Chem 270:14843–14846

    Article  PubMed  CAS  Google Scholar 

  • Dieckgraefe BK, Weems DM, Santoro SA, Alpers DH (1997) ERK and p38 MAP kinase pathways are mediators of intestinal epithelial wound-induced signal transduction. Biochem Biophys Res Commun 233:389–394

    Article  PubMed  CAS  Google Scholar 

  • Doggett TA, Swarthout JT, Jefcoat SC Jr, Wilhelm D, Dieckmann A, Angel P, Partridge NC (2002) Parathyroid hormone inhibits c-Jun N-terminal kinase activity in rat osteoblastic cells by a protein kinase A-dependent pathway. Endocrinology 143:1880–1888

    Article  PubMed  CAS  Google Scholar 

  • Garabedian M, Holick M, DeLuca H, Boyle I (1972) Control of 25-hydroxy-cholecalciferol metabolism by parathyroid glands in man. J Clin Endocrin Metab 40:152–155

    Google Scholar 

  • Gentili C, Russo de Boland A (2000) Age-related decline in mitogen-activated protein kinase phosphorylation in PTH-stimulated rat enterocytes. Exp Gerontol 35:1003–1015

    Article  PubMed  CAS  Google Scholar 

  • Gentili C, Morelli S, Russo de Boland A (2002) Involvement of IP3-Kinase and its association with c-Src in PTH-stimulated rat enterocytes. J Cell Biochem 86:773–783

    Article  PubMed  CAS  Google Scholar 

  • Gentili C, Morelli S, Boland R, Russo de Boland A (2001) Parathyroid hormone activation of MAP kinase in rat duodenal cells is mediated by 3′,5′-cyclic AMP and Ca2+. Biochim Biophys Acta 14787:1–12

    Google Scholar 

  • Gentili C, Picotto G, Morelli S, Boland R, Russo de Boland A (2003a) Effect of ageing in the early biochemical signals elicited by PTH in intestinal cells. Biochim Biophys Acta 1593:169–178

    Article  CAS  Google Scholar 

  • Gentili G, Morelli S, Russo de Boland A (2003b) Characterization of PTH/PTHrP receptor in rat duodenum: effects of ageing. J Cell Biochem 88:1157–1167

    Article  CAS  Google Scholar 

  • Gesty-Palmer D, Chen M, Reiter E, Ahn S, Nelson CD, Wang S, Eckhardt AE, Cowan CL, Spurney RF, Luttrell LM, Lefkowitz RJ (2006) Distinct beta-Arrestin-and G protein-dependent pathways for parathyroid hormone receptor-stimulated ERK1/2 activation. J Biol Chem 281:10856–10864

    Article  PubMed  CAS  Google Scholar 

  • Goke M, Kanai M, Lynch-Devaney K, Podolsky DK (1998) Rapid mitogen-activated protein kinase activation by transforming grow factor alpha in the wounded rat intestinal epithelial cells. Gastroenterology 114:697–705

    Article  PubMed  CAS  Google Scholar 

  • Homme M, Schmitt CP, Mehls O, Schaefer F (2004) Mechanisms of mitogen-activated protein kinase inhibition by parathyroid hormone in osteoblast-like cells. J Am Soc Nephrol 15:2844–2850

    Article  PubMed  CAS  Google Scholar 

  • Horiuchi N, Suda T, Sasaki S, Takahashi H, Shimazawa E (1976) Absence of regulatory effects of 1,25dihydroxyvitamin D3 on 25-hydroxyvitamin D3 metabolism in rats constantly infused with parathyroid hormone. Biochem Biophys Res Commun 73:869–875

    Article  PubMed  CAS  Google Scholar 

  • Houde M, Laprise P, Jean D, Blais M, Asselin C, Rivard N (2001) Intestinal epithelial cell differentiation involves activation of p38 mitogen-activated protein kinase that regulates the homeobox trnscription factor CDX2. J Biol Chem 276:21885–21894

    Article  PubMed  CAS  Google Scholar 

  • Inanami O, Ohta T, Ito S, Kuwabara M (1999) Elevation of intracellular calcium ions is essential for the H2O2-induced activation of SAPK/JNK but not for that of p38 and ERK in Chinese hamster V79 cells. Antioxid Redox Signal 1:501–508

    Article  PubMed  CAS  Google Scholar 

  • Kyriakis JM, Avruch J (1996) Sounding the alarm: protein kinase cascades activated by stress and inflammation. J Biol Chem 271:24313–24316

    Article  PubMed  CAS  Google Scholar 

  • Laemmli UK (1970) Cleavage of structural proteins during the assembly of the head of bacteriophage. Nature 227:680–685

    Article  PubMed  CAS  Google Scholar 

  • Lee CK, Klopp RG, Weindruch R, Prolla TA (1999) Gene expression profile of aging and its retardation by caloric restriction. Science 285:1390–1393

    Article  PubMed  CAS  Google Scholar 

  • Liu Y, Guyton KZ, Gorospe M, Xu Q, Kokkonen GC, Mock YD, Roth GS, Holbrook NJ (1996) Age-related decline in mitogen-activated protein kinase activity in epidermal growth factor-stimulated rat hepatocytes. J Biol Chem 271:36043607

    Google Scholar 

  • Macieira-Coelho A (1988) Biology of normal proliferating cells in vitro: relevance for in vivo aging. Karger, Basel

    Google Scholar 

  • Macieira-Coelho A (2003) Biology of aging. Springer, New York

    Google Scholar 

  • Mahon MJ, Bonacci TM, Divieti P, Smrcka AV (2006) A docking site for G protein betagamma subunits on the parathyroid hormone 1 receptor supports signaling through multiple pathways. Mol Endocrinol 20:136–146

    Article  PubMed  CAS  Google Scholar 

  • Massheimer V, Boland R, de Boland AR (1994) Rapid 1,25(OH)2D3 stimulation of calcium uptake by rat intestinal cells involves a dihidropyridine-sensitive cAMP-dependent pathway. Cell Signal 6:299–304

    Article  PubMed  CAS  Google Scholar 

  • Massheimer V, Picotto G, Boland R, Russo de Boland A (2000) Effect of ageing on the mechanisms of PTH-induced calcium influx in rat intestinal cells. J Cell Physiol 182:429–437

    Article  PubMed  CAS  Google Scholar 

  • Nemoto S, Sheng Z, Lin A (1998) Opposing effects of Jun kinase and p38 mitogen-activated protein kinases on cardiomyocyte hypertrophy. Mol Cell Biol 18:3518–3526

    PubMed  CAS  Google Scholar 

  • Oh C, Chang S, Yoon Y, Lee S, Lee Y, Kang S, Chun J (2000) Opposing role of mitogen-activated protein kinase subtypes, erk-1/2 and p38, in the regulation of chondrogenesis of mesenchymes. J Biol Chem 275:5613–5619

    Article  PubMed  CAS  Google Scholar 

  • Ono K, Han J (2000) The p38 signal transduction pathway activation and funcion. Cell Signal 12:1–12

    Article  PubMed  CAS  Google Scholar 

  • Papaconstantinou J (1994) Unifying model of the programmed (intrinsic) and stochastic (extrinsic) theories of aging: the stress response genes, signal transduction-redox pathways and aging. Ann N Y Acad Sci 719:195–211

    PubMed  CAS  Google Scholar 

  • Picotto G, Massheimer V, Boland R (1997) Parathyroid hormone stimulates calcium influx and the cAMP messenger system in isolated rat duodenal cells. Am J Physiol 273:C1349–C1353

    PubMed  CAS  Google Scholar 

  • Robinson MJ, Cobb MH (1997) Mitogen-activated protein kinase pathways. Curr Opin Cell Biol 9:180–186

    Article  PubMed  CAS  Google Scholar 

  • Rosenblatt M, Kronenberg H, Potts J (1989) Parathyroid hormone: physiology, chemistry, biosynthesis, secretion, metabolism and mode of action. In: Degroot LJ (eds) Endocrinology. Saunders, Philadelphia, pp 848–891

    Google Scholar 

  • Schaeffer HJ, Weber MJ (1999) Mitogen-activated protein kinases: specific messages from ubiquitous messengers. Mol Cell Biol 19:2435–2444

    PubMed  CAS  Google Scholar 

  • Seger R, Krebs EG (1995) The MAPK signaling cascade. FASEB J 9:726–735

    PubMed  CAS  Google Scholar 

  • Shimokawa N, Qiu CH, Seki T, Dikic I, Koibuchi N (2004) Phosphorylation of JNK is involved in regulation of H(+)-induced c-Jun expression. Cell Signal 16:723–729

    Article  PubMed  CAS  Google Scholar 

  • Snedecor G, Cochran W (1967) Statistical methods. Iowa State University Press, Ames, IA, pp120–134

    Google Scholar 

  • Suh Y (2001) Age-specific changes in expression, activity, and activation of the c-Jun NH2-terminal kinase and p38 mitogen-activated protein kinases by methyl methanesulfonate in rats. Mechan Ageing Develop 122:1797–1811

    Article  CAS  Google Scholar 

  • Vijg J (2000) Somatic mutations and aging: a re-evaluation. Mutat Res 447:117–135

    PubMed  CAS  Google Scholar 

  • Wada T, Joza N, Cheng HY, Sasaki T, Kozieradzki I, Bachmaier K, Katada T, Schreiber M, Wagner EF, Nishina H, Penninger JM (2004) MKK7 couples stress signalling to G2/M cell-cycle progression and cellular senescence. Nat Cell Biol 6:215–226

    Article  PubMed  CAS  Google Scholar 

  • Weiser MM (1973) Intestinal epithelial cell surface membrane glycoprotein synthesis. I. An indicator of cellular differentiation. J Biol Chem 248:2536–2541

    PubMed  CAS  Google Scholar 

  • Weston CR, Davis RJ (2002) The JNK signal transduction pathway. Curr Opin Genet Dev 12:14–21

    Article  PubMed  CAS  Google Scholar 

  • Wylie PG, Challiss RA, Blank JL (1999) Regulation of extracellular-signal regulated kinase and c-Jun N-terminal kinase by G-protein-linked muscarinic acetylcholine receptors. Biochem J 338:619–628

    Article  PubMed  CAS  Google Scholar 

  • Xia Z, Dickens M, Raingeaud J, Davis RJ, Greenberg ME (1995) Science 270:1326–1331

    Google Scholar 

  • Xiao Q, Majumdar AP (2000) Induction of transcriptional activity of AP-1 and NF-kappaB in the gastric mucosa during aging. Am J Physiol 278:G855–G865

    CAS  Google Scholar 

  • Xue L, Firestone GL, Bjeldanes LF (2005) DIM stimulates IFNgamma gene expression in human breast cancer cells via the specific activation of JNK and p38 pathways. Oncogene 24:2343–2353

    Article  PubMed  CAS  Google Scholar 

  • Yu C, Sanders MA, Basson MD (2000) Human Caco-2 motility redistributes FAK and paxillinin and activates p38 MAPK in a matrix dependent manner. Am J Physiol 278:952–966

    Google Scholar 

  • Zhen X, Wei L, Wu Q, Zhang Y, Chen Q (2001) Mitogen-activated protein kinase p38 mediates regulation of chondrocyte differentiation by parathyroid hormone. J Biol Chem 276:4879–4885

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

This research was supported by grants from the Agencia Nacional de Promoción Cientifica y Tecnológica, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) and Universidad Nacional del Sur, Argentina.

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  1. Departamento de Biología, Bioquímica y Farmacia, Universidad Nacional del Sur, San Juan 670, 8000, Bahia Blanca, Argentina

    Natalia Buzzi, Ricardo Boland & Ana Russo de Boland

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  1. Natalia Buzzi
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Correspondence to Ana Russo de Boland.

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Buzzi, N., Boland, R. & de Boland, A.R. PTH regulation of c-Jun terminal kinase and p38 MAPK cascades in intestinal cells from young and aged rats. Biogerontology 8, 189–199 (2007). https://doi.org/10.1007/s10522-006-9068-0

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