TY - JOUR
T1 - Extracellular-regulated kinase controls β-amyloid precursor protein mRNA decay
AU - Westmark, Cara J.
AU - Malter, James S.
N1 - Funding Information:
We thank the nursing staff (Infusion Center, University of Wisconsin Hospital, Madison) for drawing blood from volunteer donors and we thank members of the laboratory for their thoughtful comments. This investigation was supported by National Institutes of Health Grant RO1AG10675 (to J.S.M.) and National Institute on Aging Research Service Award AG00213 (to C.J.W.).
PY - 2001/6/20
Y1 - 2001/6/20
N2 - The precise signaling pathways which contribute to amyloid precursor protein (APP) gene expression remain incompletely characterized. We evaluated the role of protein kinases, calcium and phospholipase C (PLC) in modulating APP mRNA levels. There was a rapid 35-40% reduction in the steady state level of APP mRNA upon stimulation of peripheral blood mononuclear cells (PBMC) with phorbol 12-myristate 13-acetate (PMA), A23187 or ionomycin. However the protein kinase C (PKC), protein kinase A (PKA) or PLC pathways did not mediate these changes in APP mRNA levels. Rather, PMA or ionophore caused a rapid activation of extracellular-regulated kinase (ERK). This effect was independent of PKC and sensitive to U0126. After 4 h of PMA treatment, the remaining APP mRNA became indefinitely stable. We propose a model for the biphasic decay of APP mRNA in which ERK activation by PMA causes sequential upregulation of two APP mRNA binding proteins, nucleolin and hnRNP C. We attribute the initial rapid loss of APP mRNA to the helicase activity associated with nucleolin and later stabilization to hnRNP C binding to the 29 base instability element in the 3′-UTR of APP mRNA.
AB - The precise signaling pathways which contribute to amyloid precursor protein (APP) gene expression remain incompletely characterized. We evaluated the role of protein kinases, calcium and phospholipase C (PLC) in modulating APP mRNA levels. There was a rapid 35-40% reduction in the steady state level of APP mRNA upon stimulation of peripheral blood mononuclear cells (PBMC) with phorbol 12-myristate 13-acetate (PMA), A23187 or ionomycin. However the protein kinase C (PKC), protein kinase A (PKA) or PLC pathways did not mediate these changes in APP mRNA levels. Rather, PMA or ionophore caused a rapid activation of extracellular-regulated kinase (ERK). This effect was independent of PKC and sensitive to U0126. After 4 h of PMA treatment, the remaining APP mRNA became indefinitely stable. We propose a model for the biphasic decay of APP mRNA in which ERK activation by PMA causes sequential upregulation of two APP mRNA binding proteins, nucleolin and hnRNP C. We attribute the initial rapid loss of APP mRNA to the helicase activity associated with nucleolin and later stabilization to hnRNP C binding to the 29 base instability element in the 3′-UTR of APP mRNA.
KW - Amyloid precursor protein
KW - Extracellular-regulated kinase
KW - Gene expression
KW - Signaling
KW - mRNA stability
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U2 - 10.1016/S0169-328X(01)00112-7
DO - 10.1016/S0169-328X(01)00112-7
M3 - Article
C2 - 11406297
AN - SCOPUS:0035919129
SN - 0169-328X
VL - 90
SP - 193
EP - 201
JO - Molecular Brain Research
JF - Molecular Brain Research
IS - 2
ER -