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. 1999 Jul 15;341(Pt 2):363–369.

p44/42 mitogen-activated protein kinase is involved in the expression of ornithine decarboxylase in leukaemia L1210 cells.

F Flamigni 1, A Facchini 1, C Capanni 1, C Stefanelli 1, B Tantini 1, C M Caldarera 1
PMCID: PMC1220368  PMID: 10393094

Abstract

The involvement of p44/42 mitogen-activated protein kinase (MAPK) in the induction of ornithine decarboxylase (ODC) was investigated by using PD98059, a specific MAPK-kinase (MEK1/2) inhibitor, and other signal-transduction inhibitors. In d,l-alpha-difluoromethylornithine (DFMO)-resistant L1210 cells stimulated to grow from quiescence, treatment with PD98059 inhibited p44/42 MAPK phosphorylation and the induction of ODC activity and protein. A marked reduction of the accumulation of mature ODC mRNA and its intron-containing precursor was observed, whereas ODC turnover was hardly affected. PD98059 also reduced the content of antizyme, but not that of antizyme mRNA. U0126, a novel and more potent inhibitor of MEK1/2, provoked a dose-dependent inhibition of ODC induction at lower concentrations with respect to PD98059. Other effective inhibitors of ODC induction proved to be genistein, manumycin A, herbimycin A, LY294002, wortmannin and KT5823, suggesting the involvement of other key proteins of signal-transduction pathways, i.e. Ras, Src, phosphatidylinositol 3-kinase and cGMP-dependent protein kinase, which may have a positive impact on MAPK. Cells kept in a DFMO-free medium, and thus containing high levels of putrescine and spermidine, showed enhanced MAPK phosphorylation and lower sensitivity to PD98059, compared with cells maintained in the presence of DFMO. In conclusion, these results indicate that the activation of p44/42 MAPK may favour the expression of ODC, and that polyamines, in turn, may affect the phosphorylation state of MAPK.

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Selected References

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  1. Alessi D. R., Cuenda A., Cohen P., Dudley D. T., Saltiel A. R. PD 098059 is a specific inhibitor of the activation of mitogen-activated protein kinase kinase in vitro and in vivo. J Biol Chem. 1995 Nov 17;270(46):27489–27494. doi: 10.1074/jbc.270.46.27489. [DOI] [PubMed] [Google Scholar]
  2. Auvinen M., Paasinen-Sohns A., Hirai H., Andersson L. C., Hölttä E. Ornithine decarboxylase- and ras-induced cell transformations: reversal by protein tyrosine kinase inhibitors and role of pp130CAS. Mol Cell Biol. 1995 Dec;15(12):6513–6525. doi: 10.1128/mcb.15.12.6513. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Auvinen M., Paasinen A., Andersson L. C., Hölttä E. Ornithine decarboxylase activity is critical for cell transformation. Nature. 1992 Nov 26;360(6402):355–358. doi: 10.1038/360355a0. [DOI] [PubMed] [Google Scholar]
  4. Brown M. T., Cooper J. A. Regulation, substrates and functions of src. Biochim Biophys Acta. 1996 Jun 7;1287(2-3):121–149. doi: 10.1016/0304-419x(96)00003-0. [DOI] [PubMed] [Google Scholar]
  5. Cordelier P., Estève J. P., Bousquet C., Delesque N., O'Carroll A. M., Schally A. V., Vaysse N., Susini C., Buscail L. Characterization of the antiproliferative signal mediated by the somatostatin receptor subtype sst5. Proc Natl Acad Sci U S A. 1997 Aug 19;94(17):9343–9348. doi: 10.1073/pnas.94.17.9343. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Denhardt D. T. Signal-transducing protein phosphorylation cascades mediated by Ras/Rho proteins in the mammalian cell: the potential for multiplex signalling. Biochem J. 1996 Sep 15;318(Pt 3):729–747. doi: 10.1042/bj3180729. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Desiderio M. A., Pogliaghi G., Dansi P. Hepatocyte growth factor-induced expression of ornithine decarboxylase, c-met, and c-myc is differently affected by protein kinase inhibitors in human hepatoma cells HepG2. Exp Cell Res. 1998 Aug 1;242(2):401–409. doi: 10.1006/excr.1998.4073. [DOI] [PubMed] [Google Scholar]
  8. Don S., Bachrach U. Polyamine metabolism in normal and in virus-transformed chick embryo fibroblasts. Cancer Res. 1975 Dec;35(12):3618–3622. [PubMed] [Google Scholar]
  9. Fan G., Rillema J. A. Effect of a tyrosine kinase inhibitor, genistein, on the actions of prolactin in cultured mouse mammary tissues. Mol Cell Endocrinol. 1992 Jan;83(1):51–55. doi: 10.1016/0303-7207(92)90194-b. [DOI] [PubMed] [Google Scholar]
  10. Favata M. F., Horiuchi K. Y., Manos E. J., Daulerio A. J., Stradley D. A., Feeser W. S., Van Dyk D. E., Pitts W. J., Earl R. A., Hobbs F. Identification of a novel inhibitor of mitogen-activated protein kinase kinase. J Biol Chem. 1998 Jul 17;273(29):18623–18632. doi: 10.1074/jbc.273.29.18623. [DOI] [PubMed] [Google Scholar]
  11. Flamigni F., Faenza I., Marmiroli S., Stanic' I., Giaccari A., Muscari C., Stefanelli C., Rossoni C. Inhibition of the expression of ornithine decarboxylase and c-Myc by cell-permeant ceramide in difluoromethylornithine-resistant leukaemia cells. Biochem J. 1997 Jun 15;324(Pt 3):783–789. doi: 10.1042/bj3240783. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Flamigni F., Marmiroli S., Capanni C., Stefanelli C., Guarnieri C., Caldarera C. M. Phosphatidylinositol 3-kinase is required for the induction of ornithine decarboxylase in leukemia cells stimulated to growth. Biochem Biophys Res Commun. 1997 Oct 29;239(3):729–733. doi: 10.1006/bbrc.1997.7543. [DOI] [PubMed] [Google Scholar]
  13. Gibbs J. B., Oliff A., Kohl N. E. Farnesyltransferase inhibitors: Ras research yields a potential cancer therapeutic. Cell. 1994 Apr 22;77(2):175–178. doi: 10.1016/0092-8674(94)90308-5. [DOI] [PubMed] [Google Scholar]
  14. Hayashi S., Murakami Y., Matsufuji S. Ornithine decarboxylase antizyme: a novel type of regulatory protein. Trends Biochem Sci. 1996 Jan;21(1):27–30. [PubMed] [Google Scholar]
  15. Heby O., Persson L. Molecular genetics of polyamine synthesis in eukaryotic cells. Trends Biochem Sci. 1990 Apr;15(4):153–158. doi: 10.1016/0968-0004(90)90216-x. [DOI] [PubMed] [Google Scholar]
  16. Herbert J. M., Augereau J. M., Gleye J., Maffrand J. P. Chelerythrine is a potent and specific inhibitor of protein kinase C. Biochem Biophys Res Commun. 1990 Nov 15;172(3):993–999. doi: 10.1016/0006-291x(90)91544-3. [DOI] [PubMed] [Google Scholar]
  17. Hölttä E., Sistonen L., Alitalo K. The mechanisms of ornithine decarboxylase deregulation in c-Ha-ras oncogene-transformed NIH 3T3 cells. J Biol Chem. 1988 Mar 25;263(9):4500–4507. [PubMed] [Google Scholar]
  18. Kinoshita F., Ueno A., Miwa Y., Nishino M., Inoue H. Protein tyrosine kinase inhibitors promote amylase secretion and inhibit ornithine decarboxylase induction in sialagogue-stimulated rat parotid explants. Biochem Biophys Res Commun. 1996 Jun 5;223(1):170–174. doi: 10.1006/bbrc.1996.0864. [DOI] [PubMed] [Google Scholar]
  19. Kubota S., Kiyosawa H., Nomura Y., Yamada T., Seyama Y. Ornithine decarboxylase overexpression in mouse 10T1/2 fibroblasts: cellular transformation and invasion. J Natl Cancer Inst. 1997 Apr 16;89(8):567–571. doi: 10.1093/jnci/89.8.567. [DOI] [PubMed] [Google Scholar]
  20. Majumdar A. P. Role of tyrosine kinases in gastrin induction of ornithine decarboxylase in colonic mucosa. Am J Physiol. 1990 Oct;259(4 Pt 1):G626–G630. doi: 10.1152/ajpgi.1990.259.4.G626. [DOI] [PubMed] [Google Scholar]
  21. Manni A., Wechter R., Gilmour S., Verderame M. F., Mauger D., Demers L. M. Ornithine decarboxylase over-expression stimulates mitogen-activated protein kinase and anchorage-independent growth of human breast epithelial cells. Int J Cancer. 1997 Jan 17;70(2):175–182. doi: 10.1002/(sici)1097-0215(19970117)70:2<175::aid-ijc7>3.0.co;2-u. [DOI] [PubMed] [Google Scholar]
  22. Mar P. K., Kumar A. P., Kang D. C., Zhao B., Martinez L. A., Montgomery R. L., Anderson L., Butler A. P. Characterization of novel phorbol ester- and serum-responsive sequences of the rat ornithine decarboxylase gene promoter. Mol Carcinog. 1995 Dec;14(4):240–250. doi: 10.1002/mc.2940140404. [DOI] [PubMed] [Google Scholar]
  23. Matsufuji S., Miyazaki Y., Kanamoto R., Kameji T., Murakami Y., Baby T. G., Fujita K., Ohno T., Hayashi S. Analyses of ornithine decarboxylase antizyme mRNA with a cDNA cloned from rat liver. J Biochem. 1990 Sep;108(3):365–371. doi: 10.1093/oxfordjournals.jbchem.a123207. [DOI] [PubMed] [Google Scholar]
  24. Min A., Hasuma T., Yano Y., Matsui-Yuasa I., Otani S. Regulation of apoptosis of interleukin 2-dependent mouse T-cell line by protein tyrosine phosphorylation and polyamines. J Cell Physiol. 1995 Dec;165(3):615–623. doi: 10.1002/jcp.1041650320. [DOI] [PubMed] [Google Scholar]
  25. Mustelin T., Coggeshall K. M., Isakov N., Altman A. T cell antigen receptor-mediated activation of phospholipase C requires tyrosine phosphorylation. Science. 1990 Mar 30;247(4950):1584–1587. doi: 10.1126/science.2138816. [DOI] [PubMed] [Google Scholar]
  26. Paasinen-Sohns A., Hölttä E. Cells transformed by ODC, c-Ha-ras and v-src exhibit MAP kinase/Erk-independent constitutive phosphorylation of Sos, Raf and c-Jun activation domain, and reduced PDGF receptor expression. Oncogene. 1997 Oct 16;15(16):1953–1966. doi: 10.1038/sj.onc.1201366. [DOI] [PubMed] [Google Scholar]
  27. Packham G., Cleveland J. L. Induction of ornithine decarboxylase by IL-3 is mediated by sequential c-Myc-independent and c-Myc-dependent pathways. Oncogene. 1997 Sep 4;15(10):1219–1232. doi: 10.1038/sj.onc.1201273. [DOI] [PubMed] [Google Scholar]
  28. Pakala R., Kreisel M., Bachrach U. Polyamine metabolism and interconversion in NIH 3T3 and ras-transfected NIH 3T3 cells. Cancer Res. 1988 Jun 15;48(12):3336–3340. [PubMed] [Google Scholar]
  29. Parekh V. V., Hoffman J. L., Younoszai M. K. Effects of diabetes and difluoromethylornithine treatment on hyperplasia, activity of MAP-kinase, and activity and association with cyclin B of p34cdc2 kinase in rat jejunal mucosa. J Investig Med. 1998 Feb;46(2):76–81. [PubMed] [Google Scholar]
  30. Patel S., Wang F. H., Whiteside T. L., Kasid U. Constitutive modulation of Raf-1 protein kinase is associated with differential gene expression of several known and unknown genes. Mol Med. 1997 Oct;3(10):674–685. [PMC free article] [PubMed] [Google Scholar]
  31. Pegg A. E., Shantz L. M., Coleman C. S. Ornithine decarboxylase as a target for chemoprevention. J Cell Biochem Suppl. 1995;22:132–138. doi: 10.1002/jcb.240590817. [DOI] [PubMed] [Google Scholar]
  32. Persson L., Holm I., Heby O. Regulation of ornithine decarboxylase mRNA translation by polyamines. Studies using a cell-free system and a cell line with an amplified ornithine decarboxylase gene. J Biol Chem. 1988 Mar 5;263(7):3528–3533. [PubMed] [Google Scholar]
  33. Pyronnet S., Gingras A. C., Bouisson M., Kowalski-Chauvel A., Seva C., Vaysse N., Sonenberg N., Pradayrol L. Gastrin induces phosphorylation of eIF4E binding protein 1 and translation initiation of ornithine decarboxylase mRNA. Oncogene. 1998 Apr 30;16(17):2219–2227. doi: 10.1038/sj.onc.1201748. [DOI] [PubMed] [Google Scholar]
  34. Ruhl K. K., Pomidor M. M., Rhim J. S., Tuan R. S., Hickok N. J. Post-transcriptional suppression of human ornithine decarboxylase gene expression by phorbol esters in human keratinocytes. J Invest Dermatol. 1994 Nov;103(5):687–692. doi: 10.1111/1523-1747.ep12398542. [DOI] [PubMed] [Google Scholar]
  35. Seidel E. R., Ragan V. L. Inhibition by rapamycin of ornithine decarboxylase and epithelial cell proliferation in intestinal IEC-6 cells in culture. Br J Pharmacol. 1997 Feb;120(4):571–574. doi: 10.1038/sj.bjp.0700936. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Shantz L. M., Pegg A. E. Ornithine decarboxylase induction in transformation by H-Ras and RhoA. Cancer Res. 1998 Jul 1;58(13):2748–2753. [PubMed] [Google Scholar]
  37. Shepherd P. R., Withers D. J., Siddle K. Phosphoinositide 3-kinase: the key switch mechanism in insulin signalling. Biochem J. 1998 Aug 1;333(Pt 3):471–490. doi: 10.1042/bj3330471. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Stefanelli C., Bonavita F., Stanic' I., Mignani M., Facchini A., Pignatti C., Flamigni F., Caldarera C. M. Spermine causes caspase activation in leukaemia cells. FEBS Lett. 1998 Oct 23;437(3):233–236. doi: 10.1016/s0014-5793(98)01239-3. [DOI] [PubMed] [Google Scholar]
  39. Stefanelli C., Stanic I., Bonavita F., Flamigni F., Pignatti C., Guarnieri C., Caldarera C. M. Inhibition of glucocorticoid-induced apoptosis with 5-aminoimidazole-4-carboxamide ribonucleoside, a cell-permeable activator of AMP-activated protein kinase. Biochem Biophys Res Commun. 1998 Feb 24;243(3):821–826. doi: 10.1006/bbrc.1998.8154. [DOI] [PubMed] [Google Scholar]
  40. Tseng C. P., Verma A. K. Inhibition of 12-O-tetradecanoylphorbol-13-acetate-induced ornithine decarboxylase activity by genistein, a tyrosine kinase inhibitor. Mol Pharmacol. 1996 Aug;50(2):249–257. [PubMed] [Google Scholar]
  41. Yang D., Hayashi H., Takii T., Mizutani Y., Inukai Y., Onozaki K. Interleukin-1-induced growth inhibition of human melanoma cells. Interleukin-1-induced antizyme expression is responsible for ornithine decarboxylase activity down-regulation. J Biol Chem. 1997 Feb 7;272(6):3376–3383. doi: 10.1074/jbc.272.6.3376. [DOI] [PubMed] [Google Scholar]

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