Related Experiment Video
Updated: Mar 25, 2026
Studying Cell Cycle-regulated Gene Expression by Two Complementary Cell Synchronization Protocols
Published on: June 6, 2017
PKM2 uses control of HuR localization to regulate p27 and cell cycle progression in human glioblastoma cells
Joydeep Mukherjee1, Shigeo Ohba1, Wendy L See1
1The Department of Neurological Surgery and the Brain Tumor Research Center, Helen Diller Family Comprehensive Cancer Center, University of California-San Francisco, San Francisco, CA, 94158.
Abstract:
The M2 isoform of pyruvate kinase (PK) is upregulated in most cancers including glioblastoma. Although PKM2 has been reported to use dual kinase activities to regulate cell growth, it also interacts with phosphotyrosine (pY)-containing peptides independently of its kinase activity. The potential for PKM2 to use the binding of pY-containing proteins to control tumor growth has not been fully examined. We here describe a novel mechanism by which PKM2 interacts in the nucleus with the RNA binding protein HuR to regulate HuR sub-cellular localization, p27 levels, cell cycle progression and glioma cell growth. Suppression of PKM2 in U87, T98G and LN319 glioma cells resulted in increased p27 levels, defects in entry into mitosis, increased centrosome number, and decreased cell growth. These effects could be reversed by shRNA targeting p27. The increased levels of p27 in PKM2 knock-down cells were caused by a loss of the nuclear interaction between PKM2 and HuR, and a subsequent cytoplasmic re-distribution of HuR, which in turn led to increased cap-independent p27 mRNA translation. Consistent with these results, the alterations in p27 mRNA translation, cell cycle progression and cell growth caused by PKM2 suppression could be reversed in vitro and in vivo by suppression of HuR or p27 levels, or by introduction of forms of PKM2 that could bind pY, regardless of their kinase activity. These results define a novel mechanism by which PKM2 regulates glioma cell growth, and also define a novel set of potential therapeutic targets along the PKM2-HuR-p27 pathway.
Insights
Pyruvate kinase M2 (PKM2) regulates glioma growth by interacting with HuR, affecting p27 levels and cell cycle. Targeting this PKM2-HuR-p27 pathway offers new therapeutic strategies for glioblastoma.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Pyruvate kinase M2 (PKM2) is upregulated in cancers, including glioblastoma.
- PKM2 exhibits dual kinase activities and interacts with phosphotyrosine (pY)-containing peptides, but its role in regulating tumor growth via pY-binding is underexplored.
Purpose of the Study:
- To elucidate a novel mechanism by which PKM2 regulates glioma cell growth through interaction with HuR.
- To investigate the PKM2-HuR-p27 pathway as a potential therapeutic target in glioblastoma.
Main Methods:
- Investigated PKM2's interaction with HuR in glioma cells (U87, T98G, LN319).
- Utilized PKM2 suppression (knock-down/shRNA) and assessed effects on p27 levels, cell cycle, centrosome number, and cell growth.
- Analyzed HuR's sub-cellular localization and its impact on p27 mRNA translation.
- Evaluated the reversal of PKM2 suppression effects by targeting HuR or p27, and by introducing pY-binding PKM2 variants.
Main Results:
- PKM2 suppression increased p27 levels, caused mitotic defects, increased centrosome number, and reduced glioma cell growth.
- Loss of nuclear PKM2-HuR interaction led to HuR cytoplasmic redistribution and enhanced cap-independent p27 mRNA translation.
- Effects of PKM2 suppression were reversible by targeting HuR or p27, or by using pY-binding PKM2 variants.
Conclusions:
- PKM2 regulates glioma cell growth via a novel mechanism involving nuclear interaction with HuR, influencing HuR localization, p27 levels, and cell cycle progression.
- The PKM2-HuR-p27 pathway represents a new set of potential therapeutic targets for glioblastoma treatment.
Related Concept Videos
02:34Inhibition of Cdk Activity
02:23Abnormal Proliferation
01:23Negative Regulator Molecules
02:36DNA Damage Can Stall the Cell Cycle
02:36DNA Damage can Stall the Cell Cycle
01:27Molecular Factors Affecting Cell Division
Several proteins function as internal regulators to ensure each cell cycle stage is completed faithfully before proceeding to the next. Regulator molecules may act directly or influence the activity or production of other...