TIGAR induces p53-mediated cell-cycle arrest by regulation of RB-E2F1 complex

E. Madan, R. Gogna, P. Kuppusamy, M. Bhatt, U. Pati, A. A. Mahdi

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)516-526
Number of pages11
JournalBritish Journal of Cancer
Volume107
Issue number3
DOIs
StatePublished - Jul 24 2012
Externally publishedYes

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Retinoblastoma
Cell Cycle Checkpoints
Neoplasms
Glycolysis
Cell Cycle
Phosphorylation
G1 Phase
S Phase
Apoptosis
Cyclin D
Cyclin E
Retinoblastoma Protein
Proteins
Chromatin Immunoprecipitation
Luciferases
Heterografts
Reactive Oxygen Species
Western Blotting
Cell Proliferation
Gene Expression

All Science Journal Classification (ASJC) codes

  • Cancer Research
  • Oncology

Cite this

Madan, E., Gogna, R., Kuppusamy, P., Bhatt, M., Pati, U., & Mahdi, A. A. (2012). TIGAR induces p53-mediated cell-cycle arrest by regulation of RB-E2F1 complex. British Journal of Cancer, 107(3), 516-526. https://doi.org/10.1038/bjc.2012.260

TIGAR induces p53-mediated cell-cycle arrest by regulation of RB-E2F1 complex. / Madan, E.; Gogna, R.; Kuppusamy, P.; Bhatt, M.; Pati, U.; Mahdi, A. A.

In: British Journal of Cancer, Vol. 107, No. 3, 24.07.2012, p. 516-526.

Research output: Contribution to journalArticle

Madan, E, Gogna, R, Kuppusamy, P, Bhatt, M, Pati, U & Mahdi, AA 2012, 'TIGAR induces p53-mediated cell-cycle arrest by regulation of RB-E2F1 complex', British Journal of Cancer, vol. 107, no. 3, pp. 516-526. https://doi.org/10.1038/bjc.2012.260
Madan, E. ; Gogna, R. ; Kuppusamy, P. ; Bhatt, M. ; Pati, U. ; Mahdi, A. A. / TIGAR induces p53-mediated cell-cycle arrest by regulation of RB-E2F1 complex. In: British Journal of Cancer. 2012 ; Vol. 107, No. 3. pp. 516-526.
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