Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Paper
  • Published:

Distinct roles for p53, p27Kip1, and p21Cip1 during tumor development

Oncogene volume 23, pages 905–913 (2004)Cite this article

Abstract

Mutations in p53 and reduced expression of the Cdk inhibitor p27Kip1 are frequently observed in a wide variety of human cancers, but it is not known whether alterations in these tumor suppressors interact to influence tumor progression. To address this, we measured tumor latency and spectrum in p53 and p27 single and compound mutant mice. p53−/− (null) mice developed T-cell lymphomas and soft-tissue sarcomas, while p27−/− mice developed adenomas of the pituitary and lung, but with much longer latency. The latency for tumor development in p53−/− p27−/− and p53−/− p27+/− compound mutant mice was significantly reduced, by 15–30%, compared to single mutant p53−/− mice. The tumor spectrum in the compound mutants was similar to that of p53−/− mice, and additional tumors of diverse histotypes. In tumors from p53−/− mice, p27 protein levels were reduced to a greater extent than were mRNA levels, indicating that p27 is downregulated in tumors at the transcriptional as well as post-transcriptional levels. In contrast, mice deficient in another Cdk inhibitor p21Cip1, which is also a transcriptional target and effector of p53, showed only a marginal increase in tumor predisposition in response to ENU treatment. Thus, downregulation of p27 is a common feature in p53−/− tumors. Germline deletion of one or both alleles of p27 accelerates tumor development and associated mortality in p53−/− mice, indicating potent synergy between loss of p27 and p53. Although p21 is functionally similar to both p53 and p27, it plays a lesser role in tumor suppression. These results further highlight the highly cooperative nature of p27 and its central role in tumor suppression.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  • Adnane J, Jackson RJ, Nicosia SV, Cantor AB, Pledger WJ and Sebti SM . (2000). Oncogene, 19, 5338–5347.

  • Bearss DJ, Lee RJ, Troyer DA, Pestell RG and Windle JJ . (2002). Cancer Res., 62, 2077–2084.

  • Blain SW and Massague J . (2002). Nat. Med., 8, 1076–1078.

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

  • Bullrich F, MacLachlan TK, Sang N, Druck T, Veronese ML, Allen SL, Koff A, Heubner K, Croce CM and Giordano A . (1995). Cancer Res., 55, 1199–1205.

  • Carrano AC, Eytan E, Hershko A and Pagano M . (1999). Nat. Cell Biol., 1, 193–199.

  • Chiarle R, Budel LM, Skolnik J, Frizzera G, Chilosi M, Corato A, Pizzolo G, Magidson J, Montagnoli A, Pagano M, Maes B, Wolf-Peeters C and Inghirami G . (2000). Blood, 95, 619–626.

  • Ciaparrone M, Yamamoto H, Yao Y, Sgambato A, Cattoretti G, Tomita N, Monden T, Rotterdam H and Weinstein IB . (1998). Cancer Res., 58, 114–122.

  • Coqueret O . (2003). Trends Cell Biol., 13, 65–70.

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

  • Di Cristofano A, De Acetis M, Koff A, Cordon-Cardo C and Pandolfi PP . (2001). Nat. Genet., 27, 222–224.

  • Donehower LA, Harvey M, Slagle BL, McArthur MJ, Montgomery Jr CA, Butel JS and Bradley A . (1992). Nature, 356, 215–221.

  • El-Diery WS . (2001). Nat. Cell Biol., 3, 71–73.

  • Erlanson M, Portin C, Linderholm B, Lindh J, Roos G and Landberg G . (1998). Blood, 92, 770–777.

  • Esposito V, Baldi A, De Luca A, Groger AM, Loda M, Giordano GG, Caputi M, Baldi F, Pagano M and Giordano A . (1997). Cancer Res., 57, 3381–3385.

  • Fero ML, Randel E, Gurley KE, Roberts JM and Kemp CJ . (1998). Nature, 396, 177–180.

  • Fero ML, Rivkin M, Tasch M, Porter P, Carow CE, Firpo E, Polyak K, Tsai LH, Broudy V, Perlmutter RM, Kaushansky K and Roberts JM . (1996). Cell, 85, 733–744.

  • Franklin DS, Godfrey VL, O'Brien DA, Deng C and Xiong Y . (2000). Mol. Cell. Biol., 20, 6147–6158.

  • Geisen C, Karsunky H, Yucel R and Moroy T . (2003). Oncogene, 22, 1724–1729.

  • Harvey M, McArthur MJ, Montgomery Jr CA, Bradley A and Donehower LA . (1993). FASEB J., 7, 938–943.

  • Hollstein M, Rice K, Greenblatt MS, Soussi T, Fuchs R, Sorlie T, Hovig E, Smith-Sorensen B, Montesano R and Harris CC . (1994). Nucleic Acids Res., 22, 3551–3555.

  • Jacks T, Remington L, Williams BO, Schmitt EM, Halachmi S, Bronson RT and Weinberg RA . (1994). Curr. Biol., 4, 1–7.

  • Jackson RJ, Adnane J, Coppola D, Cantor A, Sebti SM and Pledger WJ . (2002). Oncogene, 21, 8486–8497.

  • Jackson RJ, Engelman RW, Coppola D, Cantor AB, Wharton W and Pledger WJ . (2003). Cancer Res., 63, 3021–3025.

  • Jones JM, Cui XS, Medina D and Donehower LA . (1999). Cell Growth Differ., 10, 213–222.

  • Kalbfleish JD and Prentice HM . (1980). The Statistical Analysis of Failure Time. DataWiley: New York.

    Google Scholar 

  • Kemp CJ, Wheldon T and Balmain A . (1994). Nat. Genet., 8, 66–69.

  • Kiyokawa H, Kineman RD, Manova-Todorova KO, Soares VC, Hoffman ES, Ono M, Khanam D, Hayday AC, Frohman LA and Koff A . (1996). Cell, 85, 721–732.

  • Lloyd RV, Erickson LA, Jin L, Kulig E, Qian X, Cheville JC and Scheithauer BW . (1999). Am. J. Pathol., 154, 313–323.

  • Loda M, Cukor B, Tam SW, Lavin P, Fiorentino M, Draetta GF, Jessup JM and Pagano M . (1997). Nat. Med., 3, 231–234.

  • Maronpot RR . 1999. Pathology of the Mouse, Maronpot RR, Boorman GA, Gaul U1 (eds). Cache River Press: Vienna, IL.

    Google Scholar 

  • Martin-Caballero J, Flores JM, Garcia-Palencia P and Serrano M . (2001). Cancer Res., 61, 6234–6238.

  • Martins CP and Berns A . (2002). EMBO J., 21, 3739–3748.

  • Masciullo V, Sgambato A, Pacilio C, Pucci B, Ferrandina G, Palazzo J, Carbone A, Cittadini A, Mancuso S, Scambia G and Giordano A . (1999). Cancer Res., 59, 3790–3794.

  • McAllister SS, Becker-Hapak M, Pintucci G, Pagano M and Dowdy SF . (2003). Mol. Cell. Biol., 23, 216–228.

  • Moller MB . 2000. Leukemia Lymphoma, 39, 19–27.

  • Nakayama K, Ishida N, Shirane M, Inomata A, Inoue T, Shishido N, Horii I and Loh D . (1996). Cell, 85, 707–720.

  • Nakayama K and Nakayama K . (1998). Bioessays, 20, 1020–1029.

  • Nourse J, Firpo E, Flanagan WM, Coats S, Polyak K, Lee MH, Massague J, Crabtree GR and Roberts JM . (1994). Nature, 372, 570–573.

  • Pagano M, Tam WS, Theodoras AM, Beer-Romero P, Sal GD, Chau V, Yew PR, Draetta GF and Rolf M . (1995). Science, 269, 682–685.

  • Park MS, Rosai J, Nguyen HT, Capodieci P, Cordon-Cardo C and Koff A . (1999). Proc. Natl. Acad. Sci. USA, 96, 6382–6387.

  • Philipp-Staheli J, Kim KH, Payne SR, Gurley KE, Liggitt D, Longton G and Kemp CJ . (2002). Cancer Cell, 1, 355–368.

  • Philipp-Staheli J, Payne SR and Kemp CJ . (2001). Exp. Cell Res., 264, 148–168.

  • Philipp J, Vo K, Gurley KE, Seidel K and Kemp CJ . (1999). Oncogene, 18, 4689–4698.

  • Pietenpol JA, Bohlander SK, Sato Y, Papadopoulos N, Liu B, Friedman C, Trask BJ, Roberts JM, Kinzler KW and Rowley JD et al. (1995). Cancer Res., 55, 1206–1210.

  • Piva R, Cancelli I, Cavalla P, Bortolotto S, Dominguez J, Draetta GF and Schiffer D . (1999). J. Neuropathol. Exp. Neurol., 58, 691–696.

  • Polyak K, Kato JY, Solomon MJ, Sherr CJ, Massague J and Roberts JM . (1994). Genes Dev., 8, 9–22.

  • Ponce-Castaneda MV, Lee MH, Latres E, Polyak K, Lacombe L, Montgomery K, Mathew S, Krauter K, Sheinfeld J and Massague J et al. (1995). Cancer Res., 55, 1211–1214.

  • Quintanilla-Martinez L, Thieblemont C, Fend F, Kumar S, Pinyol M, Campo E, Jaffe ES and Raffeld M . (1998). Am. J. Pathol., 153, 175–182.

  • Sanchez-Beato M, Saez AI, Martinez-Montero JC, Sol MM, Sanchez-Verde L, Villuendas R, Troncone G and Piris MA . (1997). Am. J. Pathol., 151, 151–160.

  • Schreiber E, Matthias P, Muller MM and Schaffner W . (1989). Nucleic Acids Res., 17, 6419.

  • Sherr CJ and Roberts JM . (1999). Genes Dev., 13, 1501–1512.

  • Shiohara M, El-Deiry WS, Wada M, Nakamaki T, Takeuchi S, Yang R, Vogelstein B and Koeffler HP . (1994). Blood, 84, 3781–3784.

  • Singh SP, Lipman J, Goldman H, Ellis Jr FH, Aizenman L, Cangi MG, Signoretti S, Chiaur DS, Pagano M and Loda M . (1998). Cancer Res., 58, 1730–1735.

  • Skapek SX, Rhee J, Spicer DB and Lassar AB . (1995). Science, 267, 1022–1024.

  • Slingerland J and Pagano M . (2000). J. Cell. Physiol., 183, 10–17.

  • Timme TL and Thompson TC . (1994). Biotechniques, 17, 462–463.

  • Vousden KH and Lu X . (2002). Nat. Rev. Cancer, 2, 594–604.

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

  • Waldman T, Lengauer C, Kinzler KW and Vogelstein B . (1996). Nature, 381, 713–716.

  • Wang YA, Elson A and Leder P . (1997). Proc. Natl. Acad. Sci. USA, 94, 14590–14595.

  • Yang WC, Mathew J, Velcich A, Edelmann W, Kucherlapati R, Lipkin M, Yang K and Augenlicht LH . (2001). Cancer Res., 61, 565–569.

  • Yasui W, Kudo Y, Semba S, Yokozaki H and Tahara E . (1997). Jpn. J. Cancer Res., 88, 625–629.

Download references

Acknowledgements

We thank Keri Fisher for technical assistance and Matthew Fero for valuable suggestions. This work was funded by research grants from the American Cancer Society, the NIH (CA70414), the NIEHS (ES011045), and the Life Possibilities Fund to CJK.

Author information

Author notes

  1. Jeannette Philipp-Staheli

    Present address: Geospiza, Seattle, WA, USA

  2. Kyung-Hoon Kim

    Present address: Zymogenetics, Seattle, WA, USA

Authors and Affiliations

  1. Fred Hutchinson Cancer Research Center, C1-015, 1100 Fairview Ave N., Seattle, 90109-1024, WA, USA

    Jeannette Philipp-Staheli, Kyung-Hoon Kim, Kay E Gurley, Gary Longton & Christopher J Kemp

  2. Department of Comparative Medicine, University of Washington, Seattle, WA, USA

    Denny Liggitt

Authors
  1. Jeannette Philipp-Staheli
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kyung-Hoon Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Denny Liggitt
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kay E Gurley
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Gary Longton
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Christopher J Kemp
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Christopher J Kemp.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Philipp-Staheli, J., Kim, KH., Liggitt, D. et al. Distinct roles for p53, p27Kip1, and p21Cip1 during tumor development. Oncogene 23, 905–913 (2004). https://doi.org/10.1038/sj.onc.1207220

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1207220

Keywords

This article is cited by

Search

Advanced search

Quick links