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

C J Westmark1, J S Malter

  • 1Institute on Aging and Department of Pathology and Laboratory Medicine, University of Wisconsin Medical School, Madison, WI 53792, USA.

Brain Research. Molecular Brain Research
|June 19, 2001
PubMed

Insights

Amyloid precursor protein (APP) mRNA levels rapidly decrease upon stimulation, but not through typical protein kinase C or phospholipase C pathways. Extracellular-regulated kinase (ERK) activation drives biphasic APP mRNA decay by upregulating binding proteins.

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.

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