Archives of Pharmacal Research

The Pharmaceutical Society of Korea (대한약학회)
권호 표지

Potentiation of Ceramide-Induced Apoptosis by $p27^{kip1}$ Overexpression

  • Kim Hae Jong (Division of Biochemistry, College of Pharmacy, Chung-Ang University) ;
  • Ghil Kyung Chul (Division of Biochemistry, College of Pharmacy, Chung-Ang University) ;
  • Kim Moo Sung (Division of Biochemistry, College of Pharmacy, Chung-Ang University) ;
  • Yeo Seong Hyun (Division of Biochemistry, College of Pharmacy, Chung-Ang University) ;
  • Chun Young Jin (Division of Biochemistry, College of Pharmacy, Chung-Ang University) ;
  • Kim Mie Young (Division of Biochemistry, College of Pharmacy, Chung-Ang University)
  • Published : 2005.01.01
Download PDF
⟨ Previous Next ⟩

Abstract

The cyclin-dependent kinase inhibitor$p27^{kip1}$(p27) has been implicated in the regulation of cell cycle and apoptosis. Recently, we have demonstrated that ceramide induces apoptotic cell death associated with increase in the level of p27 in HL-60 cells. In the present study, we showed that overexpression of p27 increases ceramide-induced apoptotic cell death in HL-60 cells. Furthermore, overexpression of p27 accelerated DNA fragmentation, PARP cleavage and cytochrome c release induced by ceramide. In addition, ceramide induced Sax expression independent of p27. These findings indicate that enhanced effect on apoptosis by p27 is associated with mitochondrial signaling which involves cytochrome c release.

Keywords

References

  1. Alkarain, A. and Slingerland, J., Deregulation of p27 by oncogenic signaling and its prognostic significance in breast cancer. Breast Cancer Res., 6, 13-21 (2003) https://doi.org/10.1186/bcr722
  2. Bowen, C., Birrer, M., and Gelmann, E. P., Retinoblastoma protein-mediated apoptosis after ${\gamma}$-radiation. J. Biol. Chem., 277, 44969-44979 (2002) https://doi.org/10.1074/jbc.M202000200
  3. Cheng, M., Oliver, P., Diehl, J. A., Fero, M., Roussel, M. F., Robers, J. M., and Sherr, C. J., The $p27^{kip1}$ CDK inhibitors are essential activators of cyclin D-dependent kinases in murine fibroblasts. EMBO J., 18, 1571-1583 (1999) https://doi.org/10.1093/emboj/18.6.1571
  4. Dbaibo, G. S., Pushkareva, M. Y., Jayadev, S., Schwarz, J. K., Horowitz, J. M., Obeid, L. M., Hannun, Y. A., Retinoblastoma gene product as a downstream target for a ceramidedependent pathway of growth arrest. Proc. Natl. Acad. Sci. U.S.A., 92, 1347-1351 (1995) https://doi.org/10.1073/pnas.92.5.1347
  5. El-Deiry, W. S., Tokino, T., Velculescu, V. E., Levy, D. B., Parsons, R., Trent, J. M., Lin, D., Mercer, W. E., Kinzler, K. W., and Vogelstein, B., WAF1, a potential mediator of p53 tumor suppression. Cell, 75, 817-825 (1993) https://doi.org/10.1016/0092-8674(93)90500-P
  6. Finucane, D. M., Bossy-Wetzel, E., Waterhouse, N. J., Cotter, T. G., and Green, D. R., Bax-induced caspase activation and apoptosis via cytochrome c release from mitochndria is inhibitable by Bcl-xL. J. Biol. Chem., 274, 2225-2233 (1999) https://doi.org/10.1074/jbc.274.4.2225
  7. Foster, J. S., Fernando, F. I., Ishida, N., Nakayma, K. I., and Wimalasena, J., Estrogens down-regulate $p27^{kip1}$ in breast cancer cells through skp2 and through nuclear export mediated by the ERK pathway. J. Biol. Chem., 278, 41355- 41366 (2003) https://doi.org/10.1074/jbc.M302830200
  8. Hannun, Y. A., Functions of ceramide in coordinating cellular responses to stress. Science, 274, 1855-1859 (1996) https://doi.org/10.1126/science.274.5294.1855
  9. Hannun, Y. A. and Obeid, L. M., Hannun, Y. A. and Obeid, L. M Trends Biochem. Sci., 20, 73-77 (1995) https://doi.org/10.1016/S0968-0004(00)88961-6
  10. Hawley-Nelson, P., Ciccarone, V., Gebeyhu, G., Jessee, J., and Felgner, P. L., Lipofectamine reagent: A new higher efficacy polycationic liposome transfection reagent. Focus Mol. Biol., 15, 73-79 (1993)
  11. Herr, I., Wilhelm, D., Bohler, T., Angel, P., and Debatin, K., Activation of CD95 (APO-1/Fas) signaling by ceramide mediates cancer therapy-induced apoptosis. EMBO J., 16, 6200-6208 (1997) https://doi.org/10.1093/emboj/16.20.6200
  12. Jaffrezou, J-P., Levade, T., Bettaieb, A., Andrieu, N., Bezombes, C., Maestre, N., Vermeersch, S., Rousse, A., and Laurent, B., Daunorubicin induced apoptosis: triggering of ceramide generation through sphingomyelin hydrolysis. EMBO J., 15, 2417-2424 (1996)
  13. Katayose, Y., Kim, M., Rakkar, A., Li, Z., Cowan, K. H., and Seth, P., Promoting apoptosis: A novel activity associated with the cyclin-dependent kinase inhibitor p27. Cancer Res., 57, 5441-5445 (1997)
  14. Kim, M. Y., Linardic, C., Obeid, L., and Hannun, Y. A., Identification of sphingomyelin turnover as an effector mechanism for the action of tumor necrosis factor-${\alpha}$ and ${\gamma}$-interferon. J. Biol. Chem., 266, 484-489 (1991)
  15. Kim, W. H., Ghil, K. C., Lee, J. H., Yeo, S. H., Chun, Y. J., Choi, K. H., Kim, D. K., and Kim, M. Y., Involvement of $p27^{kip1}$ in ceramide-mediated apoptosis in HL-60 cells. Cancer Lett., 151, 39-48 (2000) https://doi.org/10.1016/S0304-3835(99)00402-4
  16. Kim, H. J., Mun, J. Y., Chun, Y. J., Choi, K. H., and Kim, M. Y., Bax-dependent apoptosis induced by ceramide in HL-60 cells. FEBS Lett., 505, 264-268 (2001) https://doi.org/10.1016/S0014-5793(01)02836-8
  17. Kluck, R. M., Bossy-Wetzelm, E., Green, D. R., and Newmeyer, D. D., The release of cytochrome c from mitochondria: a primary site for Bcl-2 regulation of apoptosis. Science, 275, 1132-1136 (1997) https://doi.org/10.1126/science.275.5303.1132
  18. Li, P., Nijhawan, D., Budihardjo, I., Srinivasula, S. M., Ahmad, M., Alnemri, E. S., and Wang, X., Cytochrome c and dATPdependent formation of Apaf-1/Caspase-9 complex initiates an apoptotic protease cascade. Cell, 91, 479-489 (1997) https://doi.org/10.1016/S0092-8674(00)80434-1
  19. Liu, X., Kim, C. N., Yang, J., Jemmerson, R., and Wang, X., Induction of apoptotic program in cell-free extracts: requirement for dATP and cytochrome c. Cell, 86, 147-157 (1996) https://doi.org/10.1016/S0092-8674(00)80085-9
  20. Lloyd, R. V., Erickson, L. A., Jin, L., Kulig, E., Qian, X., Cheville, J. C., and Scheithauer, B. W., $p27^{kip1}$: A multifunctional cyclindependent kinase inhibitor with prognostic significance in human cancers. Am. J. Pathol., 154, 313-323 (1999) https://doi.org/10.1016/S0002-9440(10)65277-7
  21. Obeid, L. M., Linardic, C. M., Karolak, L. A., and Hannun, Y. A., Programmed cell death by ceramide. Science, 259, 1769- 1771 (1993) https://doi.org/10.1126/science.8456305
  22. Oh, W. J., Kim, W. H., Kang, K. H., Kim, T. Y., Kim, M. Y., and Choi, K. H., Induction of p21 during ceramide-mediated apoptosis in human hepatocarcinoma cells. Cancer Lett., 129, 215-22 (1998) https://doi.org/10.1016/S0304-3835(98)00105-0
  23. Pastorino, J. G., Chen, S. T., Tafani, M., Snyder, J. W., and Farber, J. L., The overexpression of Bax produces cell death upon induction of the mitochondrial permeability transition. J. Biol. Chem., 273, 7770-7775 (1998) https://doi.org/10.1074/jbc.273.13.7770
  24. Polyak, K., Kato, J. Y., Solomon, M. J., Sherr, C. J., Massague, J., Roberts, J. M., and Koff, A., p27kip1, a cyclin-cdk inhibitor links transforming growth factor-${\beta}$ and contact inhibition to cell cycle arrest. Genes Dev., 8, 9-22 (1994) https://doi.org/10.1101/gad.8.1.9
  25. Sherr, C. J. and Roberts, J. M., CDK inhibitors; positive and negative regulators of G1-progression. Genes Dev., 13, 1501-1512 (1999) https://doi.org/10.1101/gad.13.12.1501