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Genetic dissection of the role of p21Cip1/Waf1 in p53-mediated tumour suppression

Oncogene volume 26, pages 1645–1649 (2007)Cite this article

Abstract

Protein p21Cip1/Waf1 is transcriptionally activated by the tumour suppressor p53 and previous studies have shown that p21 plays a role in tumour suppression. However, the involvement of p21 in p53-mediated tumour suppression remains to be directly demonstrated in vivo. Tumour suppression mediated by p53 can be measured by comparing tumour susceptibility in animals carrying two (wild-type mice) or three (super-p53 mice) copies of the p53 gene. We have taken advantage of this genetically defined system to measure p53-mediated cell-cycle arrest, apoptosis and tumorigenesis, in a p21 wild-type and in a p21-null context. The absence of p21 significantly impaired the enhanced p53-mediated cell-cycle arrest characteristic of super-p53 cells, but did not affect the enhanced apoptosis. Importantly, in an experimental model of fibrosarcoma induction, the absence of p21 significantly decreased the tumour suppression benefit of super-p53 mice. We conclude that cell-cycle arrest through p21 plays a significant role in mediating p53-dependent cancer protection.

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References

  • Adnane J, Jackson RJ, Nicosia SV, Cantor AB, Pledger WJ, Sebti SM . (2000). Loss of p21WAF1/CIP1 accelerates ras oncogenesis in a transgenic/knockout mammary cancer model. Oncogene 19: 5338–5347.

    Article  CAS  Google Scholar 

  • Bearss DJ, Lee RJ, Troyer DA, Pestell RG, Windle JJ . (2002). Differential effects of p21(WAF1/CIP1) deficiency on MMTV-ras and MMTV-myc mammary tumor properties. Cancer Res 62: 2077–2084.

    CAS  PubMed  Google Scholar 

  • Bissonnette N, Hunting DJ . (1998). p21-induced cycle arrest in G1 protects cells from apoptosis induced by UV-irradiation or RNA polymerase II blockage. Oncogene 16: 3461–3469.

    Article  CAS  Google Scholar 

  • Brugarolas J, Bronson RT, Jacks T . (1998). p21 is a critical CDK2 regulator essential for proliferation control in Rb-deficient cells. J Cell Biol 141: 503–514.

    Article  CAS  Google Scholar 

  • Brugarolas J, Chandrasekaran C, Gordon JI, Beach D, Jacks T, Hannon GJ . (1995). Radiation-induced cell cycle arrest compromised by p21 deficiency. Nature 377: 552–557.

    Article  CAS  Google Scholar 

  • De la Cueva E, Garcia-Cao I, Herranz M, Lopez P, Garcia-Palencia P, Flores JM et al. (2006). Tumorigenic activity of p21(Waf1/Cip1) in thymic lymphoma. Oncogene 6: 4128–4132.

    Article  Google Scholar 

  • Deng C, Zhang P, Harper JW, Elledge SJ, Leder P . (1995). Mice lacking p21CIP1/WAF1 undergo normal development, but are defective in G1 checkpoint control. Cell 82: 675–684.

    Article  CAS  Google Scholar 

  • el-Deiry WS, Tokino T, Velculescu VE, Levy DB, Parsons R, Trent JM et al. (1993). WAF1, a potential mediator of p53 tumor suppression. Cell 75: 817–825.

    Article  CAS  Google Scholar 

  • Fan S, Chang JK, Smith ML, Duba D, Fornace Jr AJ, O'Connor PM . (1997). Cells lacking CIP1/WAF1 genes exhibit preferential sensitivity to cisplatin and nitrogen mustard. Oncogene 14: 2127–2136.

    Article  CAS  Google Scholar 

  • Fotedar R, Bendjennat M, Fotedar A . (2004). Role of p21 (WAF1) in the cellular response to UV. Cell Cycle 3: 134–137.

    Article  CAS  Google Scholar 

  • Franklin DS, Godfrey VL, O'Brien DA, Deng C, Xiong Y . (2000). Functional collaboration between different cyclin-dependent kinase inhibitors suppresses tumor growth with distinct tissue specificity. Mol Cell Biol 20: 6147–6158.

    Article  CAS  Google Scholar 

  • Garcia-Cao I, Garcia-Cao M, Martin-Caballero J, Criado LM, Klatt P, Flores JM et al. (2002). ‘Super p53’ mice exhibit enhanced DNA damage response, are tumor resistant and age normally. EMBO J 21: 6225–6235.

    Article  CAS  Google Scholar 

  • Harper JW, Adami GR, Wei N, Keyomarsi K, Elledge SJ . (1993). The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases. Cell 75: 805–816.

    Article  CAS  Google Scholar 

  • Jackson RJ, Adnane J, Coppola D, Cantor A, Sebti SM, Pledger WJ . (2002). Loss of the cell cycle inhibitors p21(Cip1) and p27(Kip1) enhances tumorigenesis in knockout mouse models. Oncogene 21: 8486–8497.

    Article  CAS  Google Scholar 

  • Jackson RJ, Engelman RW, Coppola D, Cantor AB, Wharton W, Pledger WJ . (2003). p21Cip1 nullizygosity increases tumor metastasis in irradiated mice. Cancer Res 63: 3021–3025.

    CAS  PubMed  Google Scholar 

  • Komarova EA, Kondratov RV, Wang K, Christov K, Golovkina TV, Goldblum JR et al. (2004). Dual effect of p53 on radiation sensitivity in vivo: p53 promotes hematopoietic injury, but protects from gastro-intestinal syndrome in mice. Oncogene 23: 3265–3271.

    Article  CAS  Google Scholar 

  • Lowe SW, Ruley HE . (1993). Stabilization of the p53 tumor suppressor is induced by adenovirus 5 E1A and accompanies apoptosis. Genes Dev 7: 535–545.

    Article  CAS  Google Scholar 

  • Lowe SW, Schmitt EM, Smith SW, Osborne BA, Jacks T . (1993). p53 is required for radiation-induced apoptosis in mouse thymocytes. Nature 362: 847–849.

    Article  CAS  Google Scholar 

  • Martin-Caballero J, Flores JM, Garcia-Palencia P, Collado M, Serrano M . (2004). Different cooperating effect of p21 or p27 deficiency in combination with INK4a/ARF deletion in mice. Oncogene 23: 8231–8237.

    Article  CAS  Google Scholar 

  • Martin-Caballero J, Flores JM, Garcia-Palencia P, Serrano M . (2001). Tumor susceptibility of p21(Waf1/Cip1)-deficient mice. Cancer Res 61: 6234–6238.

    CAS  PubMed  Google Scholar 

  • Palmero I, Serrano M . (2001). Induction of senescence by oncogenic ras. Methods Enzymol 333: 247–256.

    Article  CAS  Google Scholar 

  • Philipp J, Vo K, Gurley KE, Seidel K, Kemp CJ . (1999). Tumor suppression by p27Kip1 and p21Cip1 during chemically induced skin carcinogenesis. Oncogene 18: 4689–4698.

    Article  CAS  Google Scholar 

  • Poole AJ, Heap D, Carroll RE, Tyner AL . (2004). Tumor suppressor functions for the Cdk inhibitor p21 in the mouse colon. Oncogene 23: 8128–8134.

    Article  CAS  Google Scholar 

  • Samuel T, Weber HO, Funk JO . (2002). Linking DNA damage to cell cycle checkpoints. Cell Cycle 1: 162–168.

    Article  CAS  Google Scholar 

  • Strathdee G, Sansom OJ, Sim A, Clarke AR, Brown R . (2001). A role for mismatch repair in control of DNA ploidy following DNA damage. Oncogene 20: 1923–1927.

    Article  CAS  Google Scholar 

  • Topley GI, Okuyama R, Gonzales JG, Conti C, Dotto GP . (1999). p21(WAF1/Cip1) functions as a suppressor of malignant skin tumor formation and a determinant of keratinocyte stem-cell potential. Proc Natl Acad Sci USA 96: 9089–9094.

    Article  CAS  Google Scholar 

  • Vousden KH, Lu X . (2002). Live or let die: the cell's response to p53. Nat Rev Cancer 2: 594–604.

    Article  CAS  Google Scholar 

  • Vousden KH, Prives C . (2005). P53 and prognosis: new insights and further complexity. Cell 120: 7–10.

    CAS  PubMed  Google Scholar 

  • Weinberg WC, Fernandez-Salas E, Morgan DL, Shalizi A, Mirosh E, Stanulis E et al. (1999). Genetic deletion of p21WAF1 enhances papilloma formation but not malignant conversion in experimental mouse skin carcinogenesis. Cancer Res 59: 2050–2054.

    CAS  PubMed  Google Scholar 

  • Xiong Y, Hannon GJ, Zhang H, Casso D, Kobayashi R, Beach D . (1993). p21 is a universal inhibitor of cyclin kinases. Nature 366: 701–704.

    Article  CAS  Google Scholar 

  • Yang W, Velcich A, Lozonschi I, Liang J, Nicholas C, Zhuang M et al. (2005). Inactivation of p21WAF1/cip1 enhances intestinal tumor formation in Muc2-/- mice. Am J Pathol 166: 1239–1246.

    Article  CAS  Google Scholar 

  • Yang WC, Mathew J, Velcich A, Edelmann W, Kucherlapati R, Lipkin M et al. (2001). Targeted inactivation of the p21(WAF1/cip1) gene enhances Apc-initiated tumor formation and the tumor-promoting activity of a Western-style high-risk diet by altering cell maturation in the intestinal mucosal. Cancer Res 61: 565–569.

    CAS  PubMed  Google Scholar 

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Acknowledgements

We are indebted to Maribel Muñoz for excellent mouse colony management and animal care, and to Elisa Santos for mouse genotyping. AE is funded by a predoctoral fellowship from the Spanish Ministry of Education and Science (MEC). SV-M is funded by the Ramon y Cajal Program of the MEC. Work at the laboratory of MS has been funded by the CNIO, the MEC (SAF2005-03018) and by the European Union (INTACT, PROTEOMAGE).

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  1. Molecular Oncology Program, Spanish National Cancer Centre (CNIO), Madrid, Spain

    A Efeyan, M Collado, S Velasco-Miguel & M Serrano

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  1. A Efeyan
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  2. M Collado
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  3. S Velasco-Miguel
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  4. M Serrano
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Correspondence to M Serrano.

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Efeyan, A., Collado, M., Velasco-Miguel, S. et al. Genetic dissection of the role of p21Cip1/Waf1 in p53-mediated tumour suppression. Oncogene 26, 1645–1649 (2007). https://doi.org/10.1038/sj.onc.1209972

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