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Modification at HuR(S242) alters HuR localization and proliferative influence
Hyeon Ho Kim1, Xiaoling Yang, Yuki Kuwano
1Laboratory of Cellular and Molecular Biology, National Institute on Aging-IRP, National Institutes of Health, Baltimore, Maryland 21224, USA.
Cell Cycle (Georgetown, Tex.)
|October 25, 2008
Summary
Phosphorylation of Human antigen R (HuR) at serine 242 (S242) hinders its movement to the cytoplasm, impacting mRNA regulation and cell proliferation. Mutating S242 to alanine increases cytoplasmic HuR and cell growth.
Area of Science:
- Molecular Biology
- Cell Biology
- Biochemistry
Background:
- The RNA-binding protein Human antigen R (HuR) shuttles between the nucleus and cytoplasm.
- Cytoplasmic HuR stabilizes target messenger RNAs (mRNAs) and modulates their translation.
- Phosphorylation at specific sites, like serine 221 (S221) and serine 202 (S202), influences HuR's nucleocytoplasmic transport.
Purpose of the Study:
- To identify additional phosphorylation sites in the HuR hinge region that affect its cytoplasmic abundance.
- To investigate the functional consequences of altering phosphorylation at these sites, particularly S242.
Main Methods:
- Systematic mutagenesis of seven serine residues within the HuR hinge region to alanine (non-phosphorylatable).
- Analysis of HuR localization in HeLa cells under various conditions (untreated, UV stress, Cdk1 inhibition).
- Assessment of HuR-mRNA association, mRNA stability, and cell proliferation rates.
Main Results:
- The HuR(S242A) mutant showed increased cytoplasmic localization under all tested conditions.
- The phosphomimetic HuR(S242D) mutant remained predominantly nuclear.
- HuR(S242A) exhibited enhanced association with cyclin A2 and cyclin B1 mRNAs, leading to increased mRNA stability and cell proliferation.
Conclusions:
- Phosphorylation of HuR at S242 acts as a negative regulator of its cytoplasmic localization.
- S242 phosphorylation impedes HuR's role in post-transcriptional gene regulation.
- Modulating S242 phosphorylation influences cell proliferation rates.
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