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  • Original Paper
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p21Waf1/Cip1/Sdi1 induces permanent growth arrest with markers of replicative senescence in human tumor cells lacking functional p53

Oncogene volume 18, pages 2789–2797 (1999)Cite this article

Abstract

We have shown previously that wild type p53 can rapidly induce replicative senescence in EJ human bladder carcinoma cells lacking functional p53. A major effector of p53 functions is p21Waf1/Cip1/Sdi1, a potent cyclin-dependent kinase inhibitor. p21Waf1/Cip1/Sdi1 has been shown to be involved in both p53 dependent and independent control of cell proliferation, differentiation and death. To directly investigate the effects of p21Waf1/Cip1/Sid1 in the p53 response observed in EJ tumor cells, we established p21Waf1/Cip1/Sdi1 inducible lines using the tetracycline-regulatable vector system. p21Waf1/Cip1/Sdi1 induction caused irreversible cell cycle arrest in both G1 and G2/M, and diminished Cdk2 kinase activity. In addition, p21Waf1/Cip1/Sdi1 induction led to morphological alterations characteristic of cells undergoing replicative senescence with morphological, biochemical and ultrastructural markers of the senescent phenotype. Furthermore, sustained p21Waf1/Cip1/Sdi1 induction sensitized EJ cells to apoptotic cell death induced by mitomycin C, a cross-linking DNA damaging agent. These findings support the function of p21Waf1/Cip1/Sdi1 as an inducer of replicative senescence and a major mediator of this phenomenon in response to p53. Moreover, our results imply that therapeutic intervention in human cancers might be aimed at sustained elevation of p21Waf1/Cip1/Sdi1 expression.

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References

  • Agarwal M, Agarwal A, Taylor WR and Stark GR. . 1995 Proc. Natl. Acad. Sci. USA 92: 8493–8497.

  • Alpan RS and Pardee AB. . 1996 Cell Growth Differ. 7: 893–901.

  • Brown JP, Wei W and Sedivy JM. . 1997 Science 277: 831–834.

  • Brugarolas J, Chandrasekaran C, Gordon JI, Beach D, Jacks T and Hannon GJ. . 1995 Nature 377: 552–557.

  • Campisi J. . 1996 Cell 84: 497–500.

  • Canman CE, Gilmer TM, Coutts SB and Kastan MB. . 1995 Genes Dev. 9: 600–611.

  • Chen J, Jackson PK, Kirschner MW and Dutta A. . 1995 Nature 374: 386–388.

  • Datto MB, Li Y, Panus JF, Howe DJ, Xiong Y and Wang XF. . 1995 Proc. Natl. Acad. Sci. USA 92: 5545–5549.

  • Deng C, Zhang P, Harper JW, Elledge SJ and Leder P. . 1995 Cell 82: 675–684.

  • Dimri GP, Lee X, Basile G, Acosta M, Scott G, Roskelley C, Medrano EE, Linskens M, Rubelj I, Pereira-Smith O, Peacocke M and Campisi J. . 1995 Proc. Natl. Acad. Sci. USA 92: 9363–9367.

  • Dulic V, Kaufmann WK, Wilson SJ, Tlsty TD, Lees E, Harper JW, Elledge SJ and Reed SI. . 1994 Cell 76: 1013–1023.

  • Dulic V, Stein GH, Far DF and Reed SI. . 1998 Mol. Cell. Biol. 18: 546–557.

  • Duttaroy A, Qian JF, Smith JS and Wang E. . 1997 J. Cell. Biochem. 64: 434–446.

  • El-Deiry WS, Tokino T, Velculescu VE, Levy DB, Parsons R, Trent JM, Lin D, Mercer WE, Kinzler KW and Vogelstein B. . 1993 Cell 75: 817–825.

  • El-Deiry WS, Harper JW, O'Connor PM, Velculescu VE, Canman CE, Jackman J, Pietenpol JA, Burrell MH, Wang Y, Wiman KG, Mercer WE, Kaastan MB, Kohn KW, Elledge SJ, Kinzler KW and Vogelstein B. . 1994 Cancer Res. 54: 1169–1174.

  • Erhardt JA and Pittman RN. . 1998 Oncogene 16: 443–451.

  • Flores-Rozas H, Kelman Z, Dean F, Pan Z, Harper JW, Elledge SJ, O'Donnell M and Hurwitz J. . 1994 Proc. Natl. Acad. Sci. USA 91: 8655–8659.

  • Ghadially FN. . 1975 In: Ultrastructural Pathology of the Cell Butterworth: Reading, MA pp. 306–309.

    Google Scholar 

  • Gorospe M and Holbrook NJ. . 1996 Cancer Res. 56: 475–479.

  • Gossen M and Bujard H. . 1992 Proc. Natl. Acad. Sci. USA 89: 5547–5551.

  • Grana X and Reddy EP. . 1995 Oncogene 11: 211–219.

  • Guan KL, Jenkins CW, Li Y, Nichols MA, Wu X, O'Keefe CL, Matera AG and Xiong Y. . 1994 Genes Dev. 8: 2939–2952.

  • Harper JW, Adami GR, Wei N, Keyomarsi K and Elledge SJ. . 1993 Cell 75: 805–816.

  • Harper JW, Elledge SJ, Keyomarsi K, Dynlacht B, Tsai LH, Zhang P, Dobrowolski S, Bai C, Connell CL and Swindell E. . 1995 Mol. Biol. Cell 6: 387–400.

  • Jiang H, Lin J, Su Z, Collart FR, Huberman E and Fisher PB. . 1994 Oncogene 9: 3397–3407.

  • Johnson M, Dimitrov D, Vojta PJ, Barrett JC, Noda A, Pereira SO and Smith JR. . 1994 Mol. Carcinog. 11: 59–64.

  • Li R, Waga S, Hannon GJ, Beach D and Stillman B. . 1994 Nature 371: 534–537.

  • Lu Y, Yamagushi N, Yagi T and Takebe H. . 1998 Oncogene 16: 705–712.

  • Maki CG and Howley PM. . 1997 Mol. Cell. Biol. 17: 355–363.

  • Medcalf ASC, Klein-Szanto AJP and Cristofalo VJC. . 1996 Cancer Res. 56: 4582–4585.

  • Medema RH, Herrera RE, Lam F and Weinberg RA. . 1995 Proc. Natl. Acad. Sci. USA 92: 6289–6293.

  • Medema RH, Klompmaker R, Smits VAJ and Rijken G. . 1998 Oncogene 16: 431–441.

  • Michieli P, Chedid M, Lin D, Pierce JH, Mercer WE and Givol D. . 1994 Cancer Res. 54: 3391–3395.

  • Nakanishi M, Robetorye RS, Pereira-Smith OM and Smith JR. . 1995 J. Biol. Chem. 270: 17060–17063.

  • Niculescu AB, Chen X, Smeets M, Hengst L, Prives C and Reed SI. . 1998 Mol. Cell. Biol. 18: 629–643.

  • Noda A, Ning Y, Venable SF, Pereira-Smith OM and Smith JR. . 1994 Exp. Cell Res. 211: 90–98.

  • Pan ZQ, Reardon JT, Li L, Flores-Rozas H, Legerski R, Sancar A and Hurwitz J. . 1995 J. Biol. Chem. 270: 22008–22016.

  • Parker SB, Eichele G, Zhang P, Rawls A, Sands AT, Bradley A, Olsen EN, Harper JW and Elledge SJ. . 1995 Science 267: 1024–1027.

  • Pignolo RJ, Martin BG, Horton JH, Kalbach AN and Cristofalo VJ. . 1998 Exp. Gerontol. 33: 67–80.

  • Pines J. . 1995 Biochem. J. 308: 697–711.

  • Reddy EP, Reynolds RK, Santos E and Barbacid M. . 1982 Nature 300: 149–152.

  • Reynisdottir I, Polyak K, Iavarone A and Massague J. . 1995 Genes Dev. 9: 1831–1845.

  • Rieger KM, Little AF, Swart JM, Kastrinakis WV, Fitzgerald JM, Hess DT, Libertino JA and Summerhayes IC. . 1995 Br. J. Cancer 72: 683–690.

  • Sancar A. . 1994 Science 266: 1954–1956.

  • Sekiguchi T and Hunter T. . 1998 Oncogene 16: 379–379.

  • Sharma S, Schwarte-Waldhoff I, Oberhuber H and Schafer R. . 1993 Cell Growth Differ. 4: 861–869.

  • Sheikh MD, Li X, Chen J, Shao Z, Ordonez JV and Fontana JA. . 1994 Oncogene 9: 3407–3415.

  • Sherr CJ and Roberts JM. . 1995 Genes Dev. 9: 1149–1163.

  • Shivji MKK, Grey SJ, Strausfeld UP, Wood RD and Blow JJ. . 1994 Curr. Biol. 4: 1062–1068.

  • Steinman RA, Hoffman B, Iro A, Guillouf C, Liebermann DA and El-Houseini ME. . 1994 Oncogene 9: 3389–3396.

  • Sugrue MM, Shin DY, Lee SW and Aaronson SA. . 1997 Proc. Natl. Acad. Sci. USA 94: 9648–9653.

  • Tabin CJ, Bradley SM, Bargmann CI, Weinberg RA, Papageorge AG, Scolnick EM, Dhar R, Lowy DR and Chang EH. . 1982 Nature 300: 143–149.

  • Tahara H, Sato E, Noda A and Ide T. . 1995 Oncogene 10: 835–840.

  • Uhrbom L, Nister M and Westermark B. . 1997 Oncogene 15: 505–514.

  • Vlach J, Hennecke S and Amati B. . 1997 EMBO J. 16: 5334–5344.

  • Vogt M, Haggblom C, Yeargin J, Christiansen-Weber T and Haas M. . 1998 Cell Growth Differ. 9: 139–146.

  • Waga S, Hannon GJ, Beach D and Stillman B. . 1994 Nature 369: 574–578.

  • Wang E. . 1995 Cancer Res. 55: 2284–2292.

  • Wang J and Walsh K. . 1996 Science 273: 359–361.

  • Xiong Y, Zhang H and Beach D. . 1992 Cell 71: 505–514.

  • Xiong Y, Zhang H and Beach D. . 1993a Genes Dev. 7: 1572–1583.

  • Xiong Y, Hannon GJ, Zhang H, Casso D, Kobayashi R and Beach D. . 1993b Nature 366: 701–704.

  • Yang BQ, Didenko VV, Noda A, Bilyeu TA, Darlington GJ, Smith JR and Hornsby PJ. . 1995 Exp. Cell Res. 221: 126–131.

  • Yanishevsky R, Mendelsohn ML, Mayall BH and Cristofalo VJ. . 1974 J. Cell. Physio. 84: 165–170.

  • Zhang H, Xiong Y and Beach D. . 1993 Mol. Biol. Cell 4: 897–906.

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Acknowledgements

We thank DY Shin for pTet-p21 plasmid; I George of the Mount Sinai Flow Cytometry Core Facility for technical assistance with fluorescence-activated cell sorter analysis; R Gordon for electron microscopy. This work was supported in part by National Institutes of Health Grants CA66654 and the TJ Martell Foundation for Leukemia Cancer and AIDS Research (to SAA) and National Institutes of Health Grants CA66271-01 and AG08812 (to SWL). M Igarashi received support from the Forchheimer Foundation.

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  1. Derald H. Ruttenberg Cancer Center, Mount Sinai School of Medicine, New York, 10029, New York, USA

    Li Fang, Makoto Igarashi, Jennifer Leung, Mary M Sugrue & Stuart A Aaronson

  2. Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Institutes of Medicine and Harvard Medical School, Boston, 02115, Massachusetts, USA

    Sam W Lee

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Fang, L., Igarashi, M., Leung, J. et al. p21Waf1/Cip1/Sdi1 induces permanent growth arrest with markers of replicative senescence in human tumor cells lacking functional p53. Oncogene 18, 2789–2797 (1999). https://doi.org/10.1038/sj.onc.1202615

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