Extracellular-regulated kinase controls beta-amyloid precursor protein mRNA decay.

Area of Science:

• Molecular Biology
• Cell Signaling
• Gene Expression Regulation

Background:

• The regulation of amyloid precursor protein (APP) gene expression is not fully understood.
• Identifying the specific signaling pathways involved in APP mRNA modulation is crucial for understanding its role in cellular processes.

Purpose of the Study:

• To investigate the roles of protein kinases, calcium, and phospholipase C (PLC) in regulating APP mRNA levels.
• To elucidate the signaling mechanisms underlying APP mRNA dynamics in peripheral blood mononuclear cells (PBMCs).

Main Methods:

• Stimulation of PBMCs with phorbol 12-myristate 13-acetate (PMA), A23187, or ionomycin.
• Quantification of APP mRNA steady-state levels.
• Assessment of protein kinase C (PKC), protein kinase A (PKA), PLC, and extracellular-regulated kinase (ERK) pathway involvement.
• Analysis of APP mRNA stability and binding protein interactions.

Main Results:

• PMA, A23187, or ionomycin induced a 35-40% rapid reduction in APP mRNA levels.
• PKC, PKA, and PLC pathways did not mediate these changes.
• PMA or ionophore rapidly activated ERK, independent of PKC and sensitive to U0126.
• APP mRNA stability increased after 4 hours of PMA treatment.
• ERK activation led to upregulation of nucleolin and hnRNP C.

Conclusions:

• ERK activation, not PKC, PKA, or PLC, mediates the rapid decrease in APP mRNA levels.
• A model of biphasic APP mRNA decay is proposed, involving ERK-induced upregulation of nucleolin and hnRNP C.
• Nucleolin's helicase activity contributes to initial mRNA loss, while hnRNP C binding stabilizes APP mRNA via the 3'-UTR.