Amino Acids

, Volume 33, Issue 2, pp 241–252

Polyamines and mRNA stability in regulation of intestinal mucosal growth

  • J.-Y. Wang
Review Article


The mammalian intestinal epithelium is a rapidly self-renewing tissue in the body, and its homeostasis is preserved through strict regulation of epithelial cell proliferation, growth arrest, and apoptosis. Polyamines are necessary for normal intestinal mucosal growth and decreasing cellular polyamines inhibits cell proliferation and disrupts epithelial integrity. An increasing body of evidence indicates that polyamines regulate intestinal epithelial cell renewal by virtue of their ability to modulate expression of various genes and that growth inhibition following polyamine depletion results primarily from the activation of growth-inhibiting genes rather than a simple decrease in expression of growth-promoting genes. In this review article, we will focus on changes in expression of growth-inhibiting genes following polyamine depletion and further analyze in some detail the mechanisms through which mRNA stability is regulated by RNA-binding proteins.

Keywords: Intestinal epithelium – Cell proliferation and growth arrest – Posttranscriptional regulation – mRNA stability – RNA-binding proteins 



AMP-activated protein kinase


activator protein-1




coding region


cAMP responsive element


control siRNA


N1, N11-diethylnorspermdine




intestinal epithelial cell


inhibitory Smads




ornithine decarboxylase


real-time quantitative PCR


receptor-regulated Smads


siRNA targeting HuR mRNA


small interfering RNA


transforming growth factor-β


TGF-β type II receptor


TPA responsive element


3′-untranslated regions


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Angel, P, Allegretto, EA, Okino, ST, Hattori, K, Boyle, WJ, Hunter, T, Karin, M 1988Oncogene Jun encodes a sequence-specific transactivator similar to AP-1Nature332166171PubMedCrossRefGoogle Scholar
  2. Appella, E, Anderson, CW 2001Post-transcriptional modifications and activation of p53 by genotoxic stressesEur J Biochem26827642772PubMedCrossRefGoogle Scholar
  3. Attisano, L, Wrana, JL 2000Smads as transcriptional co-modulatorsCurr Opin Cell Biol12235243PubMedCrossRefGoogle Scholar
  4. Barnard, JA, Lyons, RM, Moses, HL 1990The cell biology of transforming growth factor-βBiochim Biophys Acta10327987PubMedGoogle Scholar
  5. Barnard, JA, Warwick, GJ, Gold, LI 1993Localization of transforming growth factor-β isoforms in the normal murine small intestine and colonGastroenterology1056773PubMedGoogle Scholar
  6. Bashirullah, A, Cooperstock, RL, Lipshitz, HD 2001Spatial and temporal control of RNA stabilityProc Natl Acad Sci USA9870257028PubMedCrossRefGoogle Scholar
  7. Bhattacharya, S, Ray, RM, Johnson, LR 2005STAT3-mediated transcription of Bcl-2, Mcl-1 and c-IAP2 prevents apoptosis in polyamine-depleted cellsBiochem J392335344PubMedCrossRefGoogle Scholar
  8. Brennan, CM, Steitz, JA 2001HuR and mRNA stabilityCMLS Cell Mol Life Sci58266277CrossRefGoogle Scholar
  9. Celano, P, Baylin, SB, Casero, RA 1989Polyamines differentially modulate the transcription of growth-associated genes in human colon carcinoma cellsJ Biol Chem26489228927PubMedGoogle Scholar
  10. Chan, WY, Liu, QR, Borjigin, J, Busch, H, Rennert, OM, Tease, LA, Chan, PK 1989Characterization of the cDNA encoding human nucleophosmin and studies of its role in normal and abnormal growthBiochemistry2810331039PubMedCrossRefGoogle Scholar
  11. de Silanes, IL, Zhan, M, Lal, A, Yang, X, Gorospe, M 2004Identification of a target RNA motif for RNA-binding protein HuRProc Natl Acad Sci USA10129872992CrossRefGoogle Scholar
  12. Fan, J, Yang, X, Wang, W, Wood, WH, Becker, KG, Gorospe, M 2002Global analysis of stress-regulated mRNA turnover by using cDNA arraysProc Natl Acad Sci USA991061110616PubMedCrossRefGoogle Scholar
  13. Fang, S, Jensen, JP, Ludwig, RL, Vousden, KH, Weissman, AM 2000Mdm2 is a RING finger-dependent ubiquitin protein ligase for itself and p53J Biol Chem27589458951PubMedCrossRefGoogle Scholar
  14. Franzen, P, Dijke, PT, Ichijo, H, Yamashita, H, Schulz, P, Heldin, CH, Miyazono, K 1993Cloning of a TGFβ type I receptor that forms a heteromeric complex with the TGFβ type II receptorCell75681692PubMedCrossRefGoogle Scholar
  15. Gerner, EW, Meyskens, FL 2004Polyamines and cancer: old molecules, new understandingNature Rev4781792CrossRefGoogle Scholar
  16. Gorospe, M 2003HuR in the mammalian genotoxic responseCell Cycle2412414PubMedGoogle Scholar
  17. Heinonen, M, Bono, P, Narko, K, Chang, SH, Lundin, J, Joensuu, H, Furneaux, H, Hla, T, Haglund, C, Ristimäki, A 2005Cytoplasmic HuR expression is a prognostic factor in invasive ductal breast carcinomaCancer Res6521572161PubMedCrossRefGoogle Scholar
  18. Hirai, SI, Ryseck, RP, Mechta, F, Bravo, K, Yaniv, M 1989Characterization of junD: a new member of the jun proto-oncogene familyEMBO J814331439PubMedGoogle Scholar
  19. Itoh, S, Itoh, F, Goumans, MJ, Dijke, PT 2000Signaling of transforming growth factor-β family members through Smad proteinsEur J Biochem26769546967PubMedCrossRefGoogle Scholar
  20. Johnson, LR 1988Regulation of gastrointestinal mucosal growthPhysiol Rev60456502Google Scholar
  21. Jones, BA, Gores, GJ 1997Physiology and pathophysiology of apoptosis in epithelial cells of the liver, pancreas, and intestineAm J Physiol Gastrointest Liver Physiol273G1174G1188Google Scholar
  22. Kramer, DL, Chang, BD, Chen, Y, Diegelman, P, Alm, K, Black, AR, Ronison, IB, Porter, CW 2001Polyamine depletion in human melanoma cells leads to G1 arrest associated with induction of p21WAF1/CIP1/SDI1, changes in the expression of p21-regulated genes, and a senescence-like phenotypeCancer Res6177547762PubMedGoogle Scholar
  23. Kramer, DL, Vujcic, S, Diegelman, P, Alderfer, J, Miller, JT, Black, JD, Bergeron, RJ, Porter, CW 1999Polyamine analogue induction of the p53-p21WAF1/CIP1-Rb pathway and G1 arrest in human melanoma cellsCancer Res5912781286PubMedGoogle Scholar
  24. Kurki, S, Peltonen, K, Laiho, M 2004Nucleophosmin, HDM2 and p53: players in UV damage incited nucleolar stress responseCell Cycle3976979PubMedGoogle Scholar
  25. Li, L, Li, J, Rao, JN, Li, M-L, Bass, BL, Wang, JY 1999Inhibition of polyamine synthesis induces p53 gene expression but not apoptosisAm J Physiol Cell Physiol276C946C954Google Scholar
  26. Li, L, Liu, L, Rao, JN, Esmaili, A, Strauch, ED, Bass, BL, Wang, JY 2002JunD stabilization results in inhibition of normal intestinal epithelial cell growth through p21 after polyamine depletionGastroenterology123764779PubMedCrossRefGoogle Scholar
  27. Li, L, Rao, JN, Bass, BL, Wang, JY 2001NF-κB activation and susceptibility to apoptosis following polyamine depletion in intestinal epithelial cellsAm J Physiol Gastrointest Liver Physiol280G992G1004PubMedGoogle Scholar
  28. Li, L, Rao, JN, Li, J, Patel, AR, Bass, BL, Wang, JY 2001Polyamine depletion stabilizes p53 resulting in inhibition of normal intestinal epithelial cell proliferationAm J Physiol Cell Physiol281C941C953PubMedGoogle Scholar
  29. Liu, L, Guo, X, Rao, JN, Zou, T, Marasa, BS, Chen, J, Greenspon, J, Casero, RA, Wang, JY 2006Polyamine-modulated c-Myc expression in normal intestinal epithelial cells regulates p21Cip1 transcription through a proximal promoter regionBiochem J398257267PubMedCrossRefGoogle Scholar
  30. Liu, L, Li, L, Rao, JN, Zou, TT, Zhang, HM, Boneva, D, Bernard, MS, Wang, JY 2005Polyamine-modulated expression of c-myc plays a critical role in stimulation of normal intestinal epithelial cell proliferationAm J Physiol Cell Physiol288C89C99PubMedGoogle Scholar
  31. Liu, L, Santora, R, Rao, JN, Guo, X, Zou, TT, Zhang, HM, Turner, DJ, Wang, JY 2003Activation of TGF-β/Smad signaling pathway following polyamine depletion in intestinal epithelial cellsAm J Physiol Gastrointest Liver Physiol285G1056G1067PubMedGoogle Scholar
  32. Loeffler, M, Brike, A, Winton, D, Potten, C 1993Somatic mutation, monoclonality and stochastic models of stem cell organization in the intestinal cryptJ Theor Biol160471491PubMedCrossRefGoogle Scholar
  33. Mazan-Mamczarz, K, Galban, S, de Slianes, IL, Martindale, JL, Atasoy, U, Keene, JD, Gorospe, M 2003RNA-binding protein HuR enhances p53 translation in response to ultraviolet light irradiationProc Natl Acad Sci USA10083548359PubMedCrossRefGoogle Scholar
  34. McCormack, SA, Johnson, LJ 1991Role of polyamines in gastrointestinal mucosal growthAm J Physiol Gastrointest Liver Physiol260G795G806Google Scholar
  35. Nakabeppu, Y, Ryder, K, Nathans, D 1988DNA binding activities of three murine Jun proteins: stimulation by FosCell55907915PubMedCrossRefGoogle Scholar
  36. Patel, AR, Wang, JY 1997Polyamines modulate transcription but not posttranscription of c-myc and c-jun in IEC-6 cellsAm J Physiol Cell Physiol273C1020C1029Google Scholar
  37. Patel, AR, Wang, JY 1999Polyamine depletion is associated with an increase in JunD/AP-1 activity in small intestinal crypt cellsAm J Physiol Gastrointest Liver Physiol276G441G450Google Scholar
  38. Patel, AR, Li, J, Bass, BL, Wang, JY 1998Expression of the transforming growth factor-β gene during growth inhibition following polyamine depletionAm J Physiol Cell Physiol275C590C598Google Scholar
  39. Pfarr, CM, Mechta, F, Spyrou, G, Lallemand, D, Carillo, S, Yaniv, M 1994Mouse JunD negatively regulates fibroblast growth and antagonizes transformation by rasCell76747760PubMedCrossRefGoogle Scholar
  40. Potten, AR, Loeffler, M 1990Stem cells: attributes, cycles, spirals, pitfalls, and uncertainties-lessons for and from the cryptDevelopment11010011020PubMedGoogle Scholar
  41. Potten, CS 1997Epithelial cell growth and differentiation II: intestinal apoptosisAm J Physiol Gastrointest Liver Physiol273G253G257Google Scholar
  42. Potten, CS, Wilson, JW, Booth, C 1997Regulation and significance of apoptosis in the stem cells of the gastrointestinal epitheliumStem Cells158293PubMedCrossRefGoogle Scholar
  43. Rao, JN, Li, L, Bass, BL, Wang, JY 2000Expression of the TGF-β receptor gene and sensitivity to growth inhibition following polyamine depletionAm J Physiol Cell Physiol279C1034C1044PubMedGoogle Scholar
  44. Ray, RM, Zimmerman, BJ, McCormack, SA, Patel, TB, Johnson, LR 1999Polyamine depletion arrests cell cycle and induces inhibitors p21Waf1/Cip1, p27Kip1, and p53 in IEC-6 cellsAm J Physiol Cell Physiol276C684C691Google Scholar
  45. Ryder, K, Lanahan, A, Perez-Albuerne, E, Nathans, D 1989JunD: a third member of the jun gene familyProc Natl Acad Sci USA8615001503PubMedCrossRefGoogle Scholar
  46. Schmidt-Zachmann, MS, Hugle-Dorr, B, Franke, WW 1987A constitutive nucleolar protein identified as a member of the nucleophosmin familyEMBO J618811890PubMedGoogle Scholar
  47. Seko, Y, Azmi, H, Fariss, R, Ragheb, JA 2004Selective cytoplasmic translocation of HuR and site-specific binding to the interleukin-2 mRNA are not sufficient for CD28-mediated stabilization of the mRNAJ Biol Chem2793335933367PubMedCrossRefGoogle Scholar
  48. Slee, EA, O’Connor, DJ, Lu, X 2004To die or not die: how does p53 decide?Oncogene2328092818PubMedCrossRefGoogle Scholar
  49. Tabor, CW, Tabor, TH 1984PolyaminesAnnu Rev Biochem53749790PubMedCrossRefGoogle Scholar
  50. Wang, JY, McCormack, SA, Viar, MJ, Johnson, LR 1991Stimulation of proximal small intestinal mucosal growth by luminal polyaminesAm J Physiol Gastrointest Liver Physiol261G504G511Google Scholar
  51. Wang, JY, McCormack, SA, Viar, MJ, Wang, HL, Tzen, CY, Scott, RE, Johnson, LR 1993Decreased expression of protooncogenes c-fos, c-myc, and c-jun following polyamine depletion in IEC-6 cellsAm J Physiol Gastrointest Liver Physiol265G331G338Google Scholar
  52. Wang, JY, Johnson, LR 1991Polyamines and ornithine decarboxylase during repair of duodenal mucosa after stress in ratsGastroenterology100333343PubMedGoogle Scholar
  53. Wang, JY, Johnson, LR 1994Expression of protooncogenes c-fos and c-myc in healing of gastric mucosal stress ulcersAm J Physiol Gastrointest Liver Physiol266G878G886Google Scholar
  54. Wang, W, Fan, J, Yang, X, Furer-Galban, S, de Silanes, IL, von Kobbe, C, Guo, J, Georas, SN, Foufelle, F, Hardie, DG, Carling, D, Gorospe, M 2002AMP-activated kinase regulates cytoplasmic HuRMol Cell Biol2234253436PubMedCrossRefGoogle Scholar
  55. Zawel, L, Dai, JL, Buckhaults, P, Zhou, S, Kinzler, KW, Vogelstein, B, Kern, SE 1998Human Smad3 and Smad4 are sequence specific transcription activatorsMol Cell1611617PubMedCrossRefGoogle Scholar
  56. Zhang, HM, Keledjian, KM, Rao, JN, Zou, T, Liu, L, Marasa, BS, Wang, SR, Ru, L, Strauch, ED, Wang, JY 2006Induced focal adhesion kinase expression suppresses apoptosis by activating NF-κB signaling in intestinal epithelial cellsAm J Physiol Cell Physiol290C1310C1320PubMedCrossRefGoogle Scholar
  57. Zhang, HM, Rao, JN, Guo, X, Liu, L, Zou, T, Turner, DJ, Wang, JY 2004Akt kinase activation blocks apoptosis in intestinal epithelial cells by inhibiting caspase-3 after polyamine depletionJ Biol Chem2792253922547PubMedCrossRefGoogle Scholar
  58. Zou, T, Mazan-Mamczarz, K, Rao, JN, Liu, L, Marasa, BS, Zhang, AH, Xiao, L, Pullmann, R, Gorospe, M, Wang, JY 2006Polyamine depletion increases cytoplasmic levels of RNA-binding protein HuR leading to stabilization of nucleophosmin and p53 mRNAsJ Biol Chem2811938719394PubMedCrossRefGoogle Scholar
  59. Zou, T, Rao, JN, Liu, L, Marasa, BS, Keledjian, KM, Zhang, AH, Xiao, L, Wang, JY 2005Polyamine depletion induces nucleophosmin modulating stability and transcriptional activity of p53 in intestinal epithelial cellsAm J Physiol Cell Physiol289C686C696PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • J.-Y. Wang
    • 1
  1. 1.Cell Biology Group, Departments of Surgery and PathologyUniversity of Maryland School of Medicine and Baltimore Veterans Affairs Medical CenterBaltimoreUSA

Personalised recommendations