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Updated: May 20, 2026
Analysis of Cell Cycle Position in Mammalian Cells
Published on: January 21, 2012
TIGAR induces p53-mediated cell-cycle arrest by regulation of RB-E2F1 complex
E Madan1, R Gogna, P Kuppusamy
1Department of Biochemistry, Chhatrapati Shahuji Maharaj Medical University, Lucknow 226003, India.
Background:
p53 induces cell-cycle arrest and apoptosis in cancer cells and negatively regulates glycolysis via TIGAR. Glycolysis is crucial for cancer progression although TIGAR provides protection from reactive oxygen species and apoptosis. The relation between TIGAR-mediated inhibition of glycolysis and p53 tumour-suppressor activity is unknown.
Methods:
RT-PCR, western blot, luciferase and chromatin immunoprecipitation assays were used to study TIGAR gene regulation. Co-IPP was used to determine the role of TIGAR protein in regulating the protein-protein interaction between retinoblastoma (RB) and E2F1. MCF-7 tumour xenografts were utilised to study the role of TIGAR in tumour regression.
Results:
Our study shows that TIGAR promotes p21-independent, p53-mediated G1-phase arrest in cancer cells. p53 activates the TIGAR promoter only in cells exposed to repairable doses of stress. TIGAR regulates the expression of genes involved in cell-cycle progression; suppresses synthesis of CDK-2, CDK-4, CDK-6, Cyclin D, Cyclin E and promotes de-phosphorylation of RB protein. RB de-phosphorylation stabilises the complex between RB and E2F1 thus inhibiting the entry of cell cycle from G1 phase to S phase.
Conclusion:
TIGAR mediates de-phosphorylation of RB and stabilisation of RB-E2F1 complex thus delaying the entry of cells in S phase of the cell cycle. Thus, TIGAR inhibits proliferation of cancer cells and increases drug-mediated tumour regression by promoting p53-mediated cell-cycle arrest.
Insights
Tumor protein p53 (p53) regulates cancer cell growth by controlling glycolysis via TIGAR. TIGAR stabilizes the RB-E2F1 complex, inhibiting cell cycle progression and enhancing tumor regression.
Area of Science:
- Molecular Biology
- Cancer Research
- Cell Biology
Background:
- p53 is a tumor suppressor that induces cell-cycle arrest and apoptosis, and it negatively regulates glycolysis through TIGAR.
- While TIGAR protects against reactive oxygen species and apoptosis, its role in p53's tumor-suppressor activity and glycolysis regulation remains unclear.
Purpose of the Study:
- To investigate the relationship between TIGAR-mediated glycolysis inhibition and p53's tumor-suppressor function.
- To elucidate the mechanism by which TIGAR influences cell-cycle progression and tumor regression.
Main Methods:
- Gene expression analysis using RT-PCR and Western blot.
- Assays including luciferase and chromatin immunoprecipitation to study TIGAR gene regulation.
- Co-immunoprecipitation to assess TIGAR's role in RB-E2F1 interaction and in vivo studies using MCF-7 tumor xenografts.
Main Results:
- TIGAR promotes p53-mediated G1-phase arrest independently of p21.
- p53 activates the TIGAR promoter under specific stress conditions.
- TIGAR suppresses cell-cycle gene synthesis (CDK-2, CDK-4, CDK-6, Cyclin D, Cyclin E) and promotes RB de-phosphorylation, stabilizing the RB-E2F1 complex and blocking cell cycle entry into S phase.
Conclusions:
- TIGAR inhibits cancer cell proliferation by mediating RB de-phosphorylation and stabilizing the RB-E2F1 complex, thus delaying cell cycle entry into S phase.
- TIGAR enhances drug-mediated tumor regression by promoting p53-induced cell-cycle arrest.
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