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:

Differential modulation of paclitaxel-mediated apoptosis by p21Waf1 and p27Kip1

Oncogene volume 19, pages 2423–2429 (2000)Cite this article

Abstract

The impact of the cyclin dependent kinase (CDK) inhibitors p21Waf1 and p27Kip1 on paclitaxel-mediated cytotoxicity was investigated in RKO human colon adenocarcinoma cells with the ecdysone-inducible expression of p21Waf1 or p27Kip1. Ectopic expression of p27Kip1 arrested cells at G1 phase, whereas p21Waf1 expression arrested cells at G1 and G2. Expression of p21Waf1 after paclitaxel treatment produced much greater resistance to paclitaxel than did expression of p27Kip1. We attributed this difference to the additional block at G2 induced by p21Waf1, which prevented cells from entering M phase and becoming paclitaxel susceptible. Expression of p21Waf1 inhibited p34cdc2 activity and markedly reduced paclitaxel-mediated mitotic arrest, from 87.5 to 23%. In contrast, p27Kip1 expression also inhibited p34cdc2 but reduced mitotic arrest only slightly, from 87.4 to 74.5%. We concluded that the G2 block produced by p21Waf1, but not by p27Kip1, contributed to their unequal modulation of sensitivity to paclitaxel-mediated apoptosis in RKO cells, and there is no causal relationship between paclitaxel-mediated cytotoxicity and elevation of p34cdc2 activity.

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

Abbreviations

CDK:

cyclin-dependent kinase

CDC2:

cell division control-2

References

  • Amato SF, Swart JM, Berg M, Wanebo HJ, Mehta SR and Chiles TC . 1998 Cancer Res 58: 241–247

  • Blagosklonny MV, Giannakakou P, el-Deiry WS, Kingston DG, Higgs PI, Neckers L and Fojo T . 1997 Cancer Res 57: 130–135

  • Blagosklonny MV, Schulte T, Nguyen P, Trepel J and Neckers LM . 1996 Cancer Res 56: 1851–1854

  • Cayrol C, Knibiehler M and Ducommun B . 1998 Oncogene 16: 311–320

  • Donaldson KL, Goolsby GL, Kiener PA and Wahl AF . 1994 Cell Growth Differ 5: 1041–1050

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

  • Fan Z, Lu Y, Wu X, DeBlasio A, Koff A and Mendelsohn J . 1995 J Cell Biol 131: 235–242

  • Frankel A, Buckman R and Kerbel RS . 1997 Cancer Res 57: 2388–2393

  • Haldar S, Chintapalli J and Croce CM . 1996 Cancer Res 56: 1253–1255

  • Horwitz SB . 1992 Trends Pharmacol Sci 13: 134–136

  • Ibrado AM, Liu L and Bhalla K . 1997 Cancer Res 57: 1109–1115

  • Kapoor M and Lozano G . 1998 Proc Natl Acad Sci USA 95: 2834–2837

  • Larsen JK, Munch-Petersen B, Christiansen J and Jorgensen K . 1986 Cytometry 7: 54–63

  • Lee LF, Li G, Templeton DJ and Ting JP . 1998 J Biol Chem 273: 28253–28260

  • Li W, Fan J, Banerjee D and Bertino JR . 1999 Mol Pharmacol 55: 1088–1093

  • Ling YH, Tornos C and Perez-Soler R . 1998 J Biol Chem 273: 18984–18991

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

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

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

  • Rakovitch E, Mellado W, Hall EJ, Pandita TK, Sawant S and Geard CR . 1999 Int J Radiat Oncol Biol Phys 44: 1119–1124

  • Rowinsky EK . 1997 Semin Oncol 24Suppl 19: 1–12

  • Schiff PB and Horwitz SB . 1980 Proc Natl Acad Sci USA 77: 1561–1565

  • Shen SC, Huang TS, Jee SH and Kuo ML . 1998 Cell Growth Differ 9: 23–29

  • Sorger PK, Dobles M, Tournebize R and Hyman AA . 1997 Curr Opin Cell Biol 9: 807–814

  • Strobel T, Swanson L, Korsmeyer S and Cannistra SA . 1996 Proc Natl Acad Sci USA 93: 14094–14099

  • Sumantran VN, Ealovega MW, Nunez G, Clarke MF and Wicha MS . 1995 Cancer Res 55: 2507–2510

  • Toyoshima H and Hunter T . 1994 Cell 78: 67–74

  • Uren A, Jakus J, de MF, Yeudall A, Santos E, Gutkind S and Heidaran MA . 1997 J Biol Chem 272: 21669–21672

  • van Bree C, van der Maat B, Ceha HM, Franken NA, Haveman J and Bakker PJ . 1999 J Cancer Res Clin Oncol 125: 549–555

  • Verlhac MH, de Pennart H, Maro B, Cobb MH and Clarke HJ . 1993 Dev Biol 158: 330–340

  • Wang TH, Wang HS, Ichijo H, Giannakakou P, Foster JS, Fojo T and Wimalasena J . 1998 J Biol Chem 273: 4928–4936

  • Wu X, Rubin M, Fan Z, DeBlasio T, Soos T, Koff A and Mendelsohn J . 1996 Oncogene 12: 1397–1403

  • Yu D, Jing T, Liu B, Yao J, Tan M, McDonnell TJ and Hung MC . 1998 Mol Cell 2: 581–591

Download references

Acknowledgements

The authors wish to thank Mr J Parant and Dr G Lozano for providing RKO-pVgRXR cell clone, Mrs K Ramirez and Dr NT Van for technical assistance with flow cytometry analyses, and Mr M Worley for editorial assistance with the manuscript. This work was supported by the NIH grant CA68425, the Cancer Center core grant CA16672, and an MD Anderson Cancer Center Start-up fund (to Z Fan). M Schmidt was supported by a fellowship from the Ernst Schering Research Foundation, Berlin, Germany.

Author information

Authors and Affiliations

  1. Department of Experimental Therapeutics, Division of Medicine, The University of Texas MD Anderson Cancer Center, Houston, 77030, Texas, TX, USA

    Mathias Schmidt, Yang Lu, Bolin Liu, Min Fang, John Mendelsohn & Zhen Fan

Authors
  1. Mathias Schmidt
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yang Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Bolin Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Min Fang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. John Mendelsohn
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Zhen Fan
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Schmidt, M., Lu, Y., Liu, B. et al. Differential modulation of paclitaxel-mediated apoptosis by p21Waf1 and p27Kip1. Oncogene 19, 2423–2429 (2000). https://doi.org/10.1038/sj.onc.1203546

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1203546

Keywords

This article is cited by

Search

Advanced search

Quick links