Protein kinase C stimulates HuD‐mediated mRNA stability and protein expression of neurotrophic factors and enhances dendritic maturation of hippocampal neurons in culture
Abstract
HuD protein is an RNA-binding protein involved in post-transcriptional regulation of gene expression for synaptogenesis, neuronal differentiation, and learning and memory, and is up-regulated and redistributed by a protein kinase C (PKC)-dependent pathway in neurons. Here, we show a PKC-regulated mechanism on HuD-mediated mRNA stability and expression of several neurotrophic factors (NTFs) in cultured hippocampal neurons. HuD pull-down assays showed that HuD is associated with brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), and neurotrophin (NT)-3 mRNAs. Reduction of HuD expression with short hairpin RNAs decreased BDNF, NGF, and NT-3 mRNAs and NTFs expression. Bryostatin, a PKC activator, treatment enhanced their association with HuD and increased these transcripts' stability. Bryostatin induced HuD phosphorylation, which was inhibited by Ro 32-0432, a specific PKC inhibitor. Activated PKC specifically phosphorylated coactivator-associated arginine methyltransferase 1 (CARM1), which methylates HuD and negatively modulates HuD-mRNA interactions during neuronal differentiation, and inhibited its methyltransferase activity, resulting in decrease in CARM1-mediated HuD methylation. Furthermore cotreatment of bryostatin and AMI-1, a specific CARM1 inhibitor, potentiated PKC-dependent HuD-mRNA interactions and enhanced dendritic arborization. These results demonstrate that PKC may play an important role in neuronal differentiation and synaptogenesis via stimula…
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In hippocampal neurons, activated PKC isoforms interact and phosphorylate CARM1, leading to decreased CARM1 methyltransferase activity.
“In hippocampal neurons, the study demonstrated using pathway-specific inhibitors that activated PKC isoforms interact and phosphorylate CARM1, which leads to decreased CARM1 methyltransferase activity.”
From Emerging complexity of the HuD/ELAVl4 gene; implications for neuronal development, function, and dysfunction (2013) · cites this paper as Lim and Alkon 2012
PKCε interacts with HuD, and activation of both PKC isoforms by bryostatin-1 results in HuD phosphorylation on nine residues.
“In addition, a recent study demonstrated that PKCε also interacts with HuD, and activation of both PKC isoforms by bryostatin-1 results in HuD phosphorylation on nine residues (Lim and Alkon 2012).”
From Emerging complexity of the HuD/ELAVl4 gene; implications for neuronal development, function, and dysfunction (2013) · cites this paper as Lim and Alkon 2012
Activating classical PKC isoforms and simultaneously blocking CARM1 activity potentiates HuD binding to target mRNAs and hippocampal neurite extension.
“Furthermore, activating the classical PKC isoforms and simultaneously blocking CARM1 activity potentiates HuD binding to target mRNAs and hippocampal neurite extension.”
From Emerging complexity of the HuD/ELAVl4 gene; implications for neuronal development, function, and dysfunction (2013) · cites this paper as Lim and Alkon 2012
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References 45 · Cited by 73
- Authors
- Lim, C. S., & Alkon, D. L.
- Affiliations
- West Virginia University (US)
- Corresponding author
- Lim, Chol Seung
- ORCID
- Alkon, Daniel L.
- Venue
- Hippocampus
- Publisher
- Wiley
- Published
- 2012-06-27
- Volume
- 22
- Issue
- 12
- Pages
- 2303-2319
- ISSN
- 1050-9631 (ISSN-L)
- 1098-1063
- OpenAlex
- W2122878223
- Cited by
- 73
- References
- 45
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 5 · 2023: 5 · 2022: 7 · 2021: 8 · 2020: 2 · 2019: 4 · 2018: 7 · 2017: 7 · 2016: 4 · 2015: 4 · 2014: 10 · 2013: 3
- FWCI
- 2.18
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Hippocampus (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- protein kinase C, HUD, RNA-binding proteins, mRNA stability, neurotrophic factors, brain-derived neurotrophic factor, nerve growth factor, neurotrophin-3, CARM1, protein methylation, bryostatin, hippocampal neurons, dendritic cell maturation, neuronal differentiation, synaptogenesis, post-transcriptional regulation
- MeSH terms
- ELAV-Like Protein 4, Animals, Cell Differentiation, Chromatography, High Pressure Liquid, Dendrites, Enzyme-Linked Immunosorbent Assay, Hippocampus, Nerve Growth Factors, Neurons, Protein-Arginine N-Methyltransferases, Protein Kinase C, RNA, Messenger, Mass Spectrometry, Immunoblotting, Signal Transduction, Reverse Transcriptase Polymerase Chain Reaction, RNA Stability, Electrophoretic Mobility Shift Assay, Immunoprecipitation, Rats, ELAV Proteins, Neurogenesis, Real-Time Polymerase Chain Reaction
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