Reciprocal regulation of beta-adrenergic receptor mRNA stability by mitogen activated protein kinase activation and inhibition.
Genes encoding numerous proto-oncogenes and cytokines, as well as a number of G-protein coupled receptors, are regulated post-transcriptionally at the level of mRNA stability. A common feature of all of these genes is the presence of A + U-rich elements (AREs) within their 3' untranslated regions. We, and others, have demonstrated previously that mRNAs encoding beta-adrenergic receptors (beta-ARs) are destabilized by agonist stimulation of the beta-AR/Galphas/adenylylcyclase pathway. However, in addition to PK-A, beta-ARs can also activate or inhibit mitogen activated kinase (MAPK) cascades, in a cell-type dependent basis. Recent evidence points to an important role for MAPKs in regulating the turnover of cytokine mRNAs, such as TNFalpha. We hypothesized that activation of MAPK's may also regulate beta-AR mRNA stability. The studies conducted herein demonstrate that generalized stimulation of MAPKs (JNK, p38) with anisomycin resulted in marked stabilization of beta-AR mRNA. Reciprocally, selective inhibition of JNK with SP600125 significantly decreased beta-AR mRNA half-life. Similarly, inhibition of the MEK/ERK pathway with either PD98059 or U0126 decreased beta-AR mRNA stability substantially. However, inhibition of p38 MAPK with SB203580 produced destabilization of beta-AR mRNA only at higher, non pharmacologically selective concentrations. In contrast to their effects on several other ARE containing mRNAs, inhibition of tyrosine kinases by genistein or PI3K by wortmannin, had no detectable effect on beta-AR mRNA stability. In summary, these results demonstrate for the first time that modulation of MAPK pathways can bi-directionally influence beta-AR mRNA stability.
Headley
Violetta V
VV
Department of Medicine, Division of Cardiology, University of Colorado Health Sciences Center, Denver, CO 80262, USA.
Tanveer
Rasheeda
R
Greene
Scott M
SM
Zweifach
Adam
A
Port
J David
JD
D020413:3' Untranslated Regions / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000841:Anisomycin / Q000494:pharmacology*; D000873:Anthracenes / Q000494:pharmacology; D002070:Butadienes / Q000494:pharmacology; D002460:Cell Line; D006224:Cricetinae; D004789:Enzyme Activation / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D034441:Heterogeneous-Nuclear Ribonucleoproteins / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D020871:RNA Stability / Q000187:drug effects / Q000235:genetics; D011943:Receptors, Adrenergic, beta / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects
D020413:3' Untranslated Regions; D000873:Anthracenes; D002070:Butadienes; D004791:Enzyme Inhibitors; D005419:Flavonoids; D034441:Heterogeneous-Nuclear Ribonucleoproteins; D007093:Imidazoles; D009570:Nitriles; D019384:Nucleic Acid Synthesis Inhibitors; D011725:Pyridines; D011943:Receptors, Adrenergic, beta; C113580:U 0126; C432165:pyrazolanthrone; D000841:Anisomycin; D019869:Phosphatidylinositol 3-Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one