TY - JOUR
T1 - Regulation of cyclooxgenase-2 mRNA stability by taxanes
T2 - Evidence for involvement of p38, MAPKAPK-2, and HuR
AU - Subbaramaiah, Kotha
AU - Marmo, Timothy P.
AU - Dixon, Dan A.
AU - Dannenberg, Andrew J.
PY - 2003/9/26
Y1 - 2003/9/26
N2 - Taxanes are widely used to treat malignancies and are known to modulate the transcription of several genes. We investigated the effects of taxanes (docetaxel and paclitaxel) on cyclooxygenase-2 (COX-2) transcription and mRNA stability in human mammary epithelial cells. As reported previously for paclitaxel, docetaxel stimulated COX-2 transcription by an AP-1-dependent mechanism. Treatment with taxanes also enhanced the stability of COX-2 mRNA. To define the mechanism by which taxanes stabilized COX-2 mRNA, transient transfections were carried out using luciferase expression constructs containing the COX-2 3′-untranslated region 3′-untranslated region (UTR)). The stabilizing effects of taxanes were localized to the AU-rich region of COX-2 3′-UTR. RNA binding studies indicated that taxanes stimulated the binding of HuR to the AU-rich region of the COX-2 3′k-UTR. Overexpression of antisense HuR suppressed taxane-mediated induction of COX-2 3′-UTR activity. We next investigated the signal transduction pathway responsible for taxane-mediated induction of COX-2. Taxanes enhanced protein kinase C activity; overexpressing dominant negative PKC-α suppressed taxane-mediated stimulation of both COX-2 3′-UTR and 5′-promoter activities. Interestingly, ERK1/2, JNK, and p38 MAPKs were important for taxane-mediated activation of COX-2 transcription, but only p38 MAPK appeared to be responsible for the increase in COX-2 mRNA stability. MAPKAPK-2, a known target of p38 MAPK, contributed to increased COX-2 mRNA stability following taxane treatment. SB 202190, a selective p38 MAPK inhibitor, and dexamethasone suppressed taxane-mediated stimulation of the COX-2 3′-UTR and binding of HuR. Taken together, these data indicate that taxanes induce COX-2 by stimulating both transcription and mRNA stability. To the best of our knowledge, this is the first evidence that taxanes can promote stabilization of mRNA in addition to modulating gene transcription.
AB - Taxanes are widely used to treat malignancies and are known to modulate the transcription of several genes. We investigated the effects of taxanes (docetaxel and paclitaxel) on cyclooxygenase-2 (COX-2) transcription and mRNA stability in human mammary epithelial cells. As reported previously for paclitaxel, docetaxel stimulated COX-2 transcription by an AP-1-dependent mechanism. Treatment with taxanes also enhanced the stability of COX-2 mRNA. To define the mechanism by which taxanes stabilized COX-2 mRNA, transient transfections were carried out using luciferase expression constructs containing the COX-2 3′-untranslated region 3′-untranslated region (UTR)). The stabilizing effects of taxanes were localized to the AU-rich region of COX-2 3′-UTR. RNA binding studies indicated that taxanes stimulated the binding of HuR to the AU-rich region of the COX-2 3′k-UTR. Overexpression of antisense HuR suppressed taxane-mediated induction of COX-2 3′-UTR activity. We next investigated the signal transduction pathway responsible for taxane-mediated induction of COX-2. Taxanes enhanced protein kinase C activity; overexpressing dominant negative PKC-α suppressed taxane-mediated stimulation of both COX-2 3′-UTR and 5′-promoter activities. Interestingly, ERK1/2, JNK, and p38 MAPKs were important for taxane-mediated activation of COX-2 transcription, but only p38 MAPK appeared to be responsible for the increase in COX-2 mRNA stability. MAPKAPK-2, a known target of p38 MAPK, contributed to increased COX-2 mRNA stability following taxane treatment. SB 202190, a selective p38 MAPK inhibitor, and dexamethasone suppressed taxane-mediated stimulation of the COX-2 3′-UTR and binding of HuR. Taken together, these data indicate that taxanes induce COX-2 by stimulating both transcription and mRNA stability. To the best of our knowledge, this is the first evidence that taxanes can promote stabilization of mRNA in addition to modulating gene transcription.
UR - http://www.scopus.com/inward/record.url?scp=0141844522&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0141844522&partnerID=8YFLogxK
U2 - 10.1074/jbc.M301481200
DO - 10.1074/jbc.M301481200
M3 - Article
C2 - 12826679
AN - SCOPUS:0141844522
SN - 0021-9258
VL - 278
SP - 37637
EP - 37647
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 39
ER -