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TIGAR induces p53-mediated cell-cycle arrest by regulation of RB-E2F1 complex.
Br J Cancer. 2012 Jul 24; 107(3):516-26.BJ

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.

Authors+Show Affiliations

Department of Biochemistry, Chhatrapati Shahuji Maharaj Medical University, Lucknow 226003, India.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22782351

Citation

Madan, E, et al. "TIGAR Induces P53-mediated Cell-cycle Arrest By Regulation of RB-E2F1 Complex." British Journal of Cancer, vol. 107, no. 3, 2012, pp. 516-26.
Madan E, Gogna R, Kuppusamy P, et al. TIGAR induces p53-mediated cell-cycle arrest by regulation of RB-E2F1 complex. Br J Cancer. 2012;107(3):516-26.
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), 516-26. https://doi.org/10.1038/bjc.2012.260
Madan E, et al. TIGAR Induces P53-mediated Cell-cycle Arrest By Regulation of RB-E2F1 Complex. Br J Cancer. 2012 Jul 24;107(3):516-26. PubMed PMID: 22782351.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - TIGAR induces p53-mediated cell-cycle arrest by regulation of RB-E2F1 complex. AU - Madan,E, AU - Gogna,R, AU - Kuppusamy,P, AU - Bhatt,M, AU - Pati,U, AU - Mahdi,A A, Y1 - 2012/07/10/ PY - 2012/7/12/entrez PY - 2012/7/12/pubmed PY - 2013/1/9/medline SP - 516 EP - 26 JF - British journal of cancer JO - Br J Cancer VL - 107 IS - 3 N2 - 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. SN - 1532-1827 UR - https://www.unboundmedicine.com/medline/citation/22782351/TIGAR_induces_p53_mediated_cell_cycle_arrest_by_regulation_of_RB_E2F1_complex_ L2 - https://doi.org/10.1038/bjc.2012.260 DB - PRIME DP - Unbound Medicine ER -