Tristetrapolin Binds to the COX-2 mRNA 3’ Untranslated Region in Cancer Cells

Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 525)


Consistent evidence of several types indicates that the inducible cyclooxygenase (COX-2) can promote the multi-step sequence of events that lead to colon cancer [1,2]. Levels of COX-2 are increased in 85-90% of human colorectal adencarcinoma [3]. It also is expressed in cancers of the stomach [4], esophagus [5], pancreas [6], prostate [7], lung [8], and breast [9]. Whereas it is clear that COX-2 plays an important role in the initiation of colon cancer, the mechanisms that lead to its over-expression have not been fully elucidated. COX-2 expression is regulated at the transcriptional level in response to cytokines [10] and oncogenic signaling pathways [11]. Also, post-transcriptional mechanisms have been shown to play a role in the regulation of COX-2 expression during carcinogenesis [12], and to increase [13] or decrease [14] COX-2 mRNA stability. The 3’ UTR of COX-2 mRNA contains 22 copies of a conserved AU-rich sequence element (ARE), the AUUUA pentamer. This pentamer, frequently located in or near a U rich region, has been associated with the regulation of the stability of a number of mRNAs, including those of proto-oncogenes and cytokines. A number of ARE-binding proteins have been identified, including HuR, AUF- 1/hnRNPD, TIA-1, and tristetraprolin, that can exert either positive or negative effects on stability, translation and subcellular localization of the mRNA [15, 16, 17].


Familial Adenomatous Polyposis Oncogenic Signaling Pathway Inducible Cyclooxygenase Human Colorectal Adenocarcinoma Cell Line Factor Alpha mRNA 
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  1. 1.
    Giardiello FM, Hamilton SR, Krush AJ, Piantadosi S, Hylind LM, Celano P, Booker SV, Robinson CR, Offerhaus GJ. Treatment of colonic and rectal adenomas with sulindac in familial adenomatous polyposis. N Engl J Med 993; 328, 1313–6.Google Scholar
  2. 2.
    Oshima M, Dinchuk JE, Kargman SL, Oshima H, Hancock B, Kwong E, Trzaskos JM, Evans JF, Taketo MM. Suppression of intestinal polyposis in Apc delta716 knockout mice by inhibition of cyclooxygenase 2 (COX-2). Cell 1996; 87, 803–9.PubMedCrossRefGoogle Scholar
  3. 3.
    Eberhart CE, Coffey RJ, Radhika A, Giardiello, FM, Ferrenbach S, DuBois RN. Up-regulation of cyclooxygenase 2 gene expression in human colorectal adenomas and adenocarcinomas. Gastorenterology 1994; 107, 1183–8.Google Scholar
  4. 4.
    Ristimaki A, Honkanen N, Jankala H, Sipponen P, Harkonen M. Expression of cyclooxygenase-2 in human gastric carcinoma. Cancer Res 1997; 57, 1276–1280.PubMedGoogle Scholar
  5. 5.
    Zimmermann KC, Sarbia M, Weber AA, Borchard F, Gabbert HE, Schror K. Cyclooxygenase-2 expression in human esophageal carcinoma. Cancer Res 1999; 59, 198–204.PubMedGoogle Scholar
  6. 6.
    Molina MA, Sitja-Arnau M, Lemoine MG, Frazier ML, Sinicrope FA. Increased cyclooxygenase-2 expression in human pancreatic carcinomas and cell lines: growth inhibition by nonsteroidal anti-inflammatory drugs. Cancer Res 1999; 59, 4356–62.PubMedGoogle Scholar
  7. 7.
    Yoshimura R, Sano H, Masuda C, Kawamura M, Tsubouchi Y, Chargui J, Yoshimura N, Hla T, Wada S. Expression of cyclooxygenase-2 in prostate carcinoma. Cancer 2000; 89, 589–96.PubMedCrossRefGoogle Scholar
  8. 8.
    Wolff H, Saukkonen K, Anttila S, Karjalainen A, Vainio H, Ristimaki A. Expression of cyclooxygenase-2 in human lung carcinoma. Cancer Res 1998; 58, 4997–5001.PubMedGoogle Scholar
  9. 9.
    Soslow RA, Dannenberg AJ, Rush D, Woerner BM, Khan KN, Masferrer J, Koki AT. COX-2 is expressed in human pulmonary, colonic, and mammary tumors. Cancer 2000; 89, 2637–45.PubMedCrossRefGoogle Scholar
  10. 10.
    Barrios-Rodiles M, Tiraloche G, Chadee K. Lipopolysaccharide modulates cyclooxygenase-2 transcriptionally and posttranscriptionally in human macrophages independently from endogenous IL-1 beta and TNF-alpha. J Immunol 1999; 163, 963–9.PubMedGoogle Scholar
  11. 11.
    Xie W, Herschman HR. v-src induces prostaglandin synthase 2 gene expression by activation of the c-Jun N-terminal kinase and the c-Jun transcription factor. J Biol Chem 1995; 270, 27622–8.PubMedCrossRefGoogle Scholar
  12. 12.
    Zhang Z, Sheng H, Shao J, Beauchamp RD, DuBois RN. Posttranscriptional regulation of cyclooxygenase-2 in rat intestinal epithelial cells. Neoplasia 2000; 2, 523–30.PubMedCrossRefGoogle Scholar
  13. 13.
    Ridley SH, Dean JL, Sarsfield SJ, Brook M, Clark AR, Saklatvala J. A p38 MAP kinase inhibitor regulates stability of interleukin-1-induced cyclooxygenase-2 mRNA. FEBS Lett 1998; 439, 75–80.PubMedCrossRefGoogle Scholar
  14. 14.
    Lasa M, Brook M, Saklatvala J, Clark AR. Dexamethasone destabilizes cyclooxygenase 2 mRNA by inhibiting mitogen-activated protein kinase p38. Mol Cell Biol 2001; 21, 771–80.PubMedCrossRefGoogle Scholar
  15. 15.
    Dixon DA, Kaplan CD, McIntyre TM, Zimmerman GA, Prescott SM. Posttranscriptional control of cyclooxygenase-2 gene expression. The role of the 3′-untranslated region. J Biol Chem 2000; 275, 11750–11757.PubMedCrossRefGoogle Scholar
  16. 16.
    Aghib DF, Bishop JM, Ottolenghi S, Guerrasio A, Serra A, Saglio G. A 3′ truncation of MYC caused by chromosomal translocation in a human T-cell leukemia increases mRNA stability. Oncogene 1990; 5, 707–11.PubMedGoogle Scholar
  17. 17.
    Raymond V, Atwater JA, Verma IM. Removal of an mRNA destabilizing element correlates with the increased oncogenicity of proto-oncogene fos. Oncogene Res 1989; 5, 1–12.PubMedGoogle Scholar
  18. 18.
    DuBois RN, Bishop PR, Graves-Deal R, Coffey RJ. Transforming growth factor alpha regulation of two zinc finger-containing immediate early response genes in intestine. Cell Growth Differ 1995; 6, 523–9.PubMedGoogle Scholar
  19. 19.
    Raghavan A, Robison RL, McNabb J, Miller CR, Williams DA, Bohjanen PR. HuA and Tristetraprolin are induced following T cell activation and display distinct but overlapping RNA-binding specificities. J Biol Chem 2001; 15, 15.Google Scholar
  20. 20.
    Carballo E, Lai WS, Blackshear PJ. Feedback inhibition of macrophage tumor necrosis factor-alpha production by tristetraprolin. Science 1998; 281, 1001–5.PubMedCrossRefGoogle Scholar
  21. 21.
    Mahtani KR, Brook M, Dean JL, Sully G, Saklatvala J, Clark AR. Mitogen-activated protein kinase p38 controls the expression and posttranslational modification of tristetraprolin, a regulator of tumor necrosis factor alpha mRNA stability. Mol Cell Biol 2001; 21, 6461–9.PubMedCrossRefGoogle Scholar

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© Springer Science+Business Media New York 2003

Authors and Affiliations

  1. 1.Division of Clinical PharmacologyVanderbilt UniversityNashvilleUSA
  2. 2.School of Medicine, Department of SurgeryVanderbilt UniversityNashvilleUSA
  3. 3.Division of Clinical PharmacologyVanderbilt University School of Medicine, The Vanderbilt-Ingram Cancer CenterNashvilleUSA
  4. 4.School of Medicine, Department of PharmacologyVanderbilt UniversityNashvilleUSA

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