Regulation of the mRNA-binding protein AUF1 by activation of the beta-adrenergic receptor signal transduction pathway.
In both cell culture based model systems and in the failing human heart, beta-adrenergic receptors ( beta-AR) undergo agonist-mediated down-regulation. This decrease correlates closely with down-regulation of its mRNA, an effect regulated in part by changes in mRNA stability. Regulation of mRNA stability has been associated with mRNA-binding proteins that recognize A + U-rich elements within the 3'-untranslated regions of many mRNAs encoding proto-oncogene and cytokine mRNAs. We demonstrate here that the mRNA-binding protein, AUF1, is present in both human heart and in hamster DDT1-MF2 smooth muscle cells and that its abundance is regulated by beta-AR agonist stimulation. In human heart, AUF1 mRNA and protein was significantly increased in individuals with myocardial failure, a condition associated with increases in the beta-adrenergic receptor agonist norepinephrine. In the same hearts, there was a significant decrease (approximately 50%) in the abundance of beta1-AR mRNA and protein. In DDT1-MF2 cells, where agonist-mediated destabilization of beta2-AR mRNA was first described, exposure to beta-AR agonist resulted in a significant increase in AUF1 mRNA and protein (approximately 100%). Conversely, agonist exposure significantly decreased (approximately 40%) beta2-adrenergic receptor mRNA abundance. Last, we demonstrate that AUF1 can be immunoprecipitated from polysome-derived proteins following UV cross-linking to the 3'-untranslated region of the human beta1-AR mRNA and that purified, recombinant p37AUF1 protein also binds to beta1-AR 3'-untranslated region mRNA.
Pende
A
A
University of Colorado Health Sciences Center, Division of Cardiology, Denver, 80262, USA.
Tremmel
K D
KD
DeMaria
C T
CT
Blaxall
B C
BC
Minobe
W A
WA
Sherman
J A
JA
Bisognano
J D
JD
Bristow
M R
MR
Brewer
G
G
Port
J
J
D001483:Base Sequence; D017931:DNA Primers / Q000737:chemistry; D019204:GTP-Binding Proteins / Q000502:physiology; D005786:Gene Expression Regulation; D006333:Heart Failure / Q000378:metabolism; D000081035:Heterogeneous Nuclear Ribonucleoprotein D0; D034502:Heterogeneous-Nuclear Ribonucleoprotein D; D006801:Humans; D008969:Molecular Sequence Data; D009130:Muscle, Smooth / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism*; D011132:Polyribosomes / Q000378:metabolism / Q000528:radiation effects; D000090063:Proto-Oncogene Mas; D012333:RNA, Messenger / Q000737:chemistry / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000378:metabolism*; D011943:Receptors, Adrenergic, beta / Q000502:physiology*; D011994:Recombinant Proteins; D015398:Signal Transduction; D014466:Ultraviolet Rays
D017931:DNA Primers; C000630986:HNRNPD protein, human; D000081035:Heterogeneous Nuclear Ribonucleoprotein D0; D034502:Heterogeneous-Nuclear Ribonucleoprotein D; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D011943:Receptors, Adrenergic, beta; D011994:Recombinant Proteins; D019204:GTP-Binding Proteins