Abstract
The cyclin-dependent kinase inhibitor p27KIP1 is a crucial component of the mammalian restriction point, and as such is subject to multiple regulatory mechanisms. It has recently been shown that the abundance of p27KIP1 is also regulated during apoptosis; p27KIP1 is cleaved by a Z-VAD-fmk-sensitive caspase during apoptosis induced by growth factor deprivation in endothelial cells, and also following exposure of myeloid leukaemia cells to etoposide. Here, we investigate p27KIP1 regulation in B- and T-lymphoid cells undergoing apoptosis. We observe that p27KIP1 is down-regulated following exposure to a variety of apoptotic stimuli including an agonistic anti-Fas antibody, cycloheximide and etoposide. Further investigation revealed the existence of two different routes of p27KIP1 regulation in lymphoid cells undergoing apoptosis. The first pathway is utilized by lymphoid cells stimulated through Fas, is abrogated in a caspase-8-deficient T-cell line, and is blocked by the caspase inhibitors Z-VAD-fmk and Boc-D-fmk. In contrast, the loss of p27KIP1 in cells exposed to cycloheximide and etoposide occurs in the absence of caspase-8 or any Z-VAD-fmk- or Boc-D-fmk-sensitive caspase activities. Thus the down-regulation of p27KIP1 is a common occurrence in lymphoid cells undergoing apoptosis but, depending on the apoptotic trigger, this can be affected by two different mechanisms.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Brown TL, Patil S, Cianci CD, Morrow JS and Howe PH. . 1999 J. Biol. Chem. 274: 23256–23262.
Cannell EJ, Farrell PJ and Sinclair AJ. . 1998 FEBS Lett. 439: 297–301.
Chen L, Marechal V, Moreau J, Levine AJ and Chen J. . 1997 J. Biol. Chem. 272: 22966–22973.
Craig C, Wersto R, Kim M, Ohri E, Li ZW, Katayose D, Lee SJ, Trepel J, Cowan K and Seth P. . 1997 Oncogene 14: 2283–2289.
Ekert PG, Silke J and Vaux DL. . 1999 Cell Death and Differ. 6: 1081–1086.
Erhardt P, Tomaselli KJ and Cooper GM. . 1997 J. Biol. Chem. 272: 15049–15052.
Eymin B, Haugg M, Droin N, Sordet O, Dimanche-Boitrel M-T and Solary E. . 1999a Oncogene 18: 1411–1418.
Eymin B, Sordet O, Droin N, Munsch B, Haugg M, Van de Craen M, Vandenabeele P and Solary E. . 1999b Oncogene 18: 4839–4847.
Hiromura K, Pippin JW, Fero ML, Roberts JM and Shankland SJ. . 1999 J. Clin. Invest. 103: 597–604.
Juo P, Kuo CJ, Yuan J and Blenis J. . 1998 Curr. Biol. 8: 1001–1008.
Kawamata S, Sakaida H, Hori T, Maeda M and Uchiyama T. . 1998 Blood 91: 561–569.
King W, Powell A, Raab-Traub N, Hawke M and Keiff E. . 1980 J. Virol. 36: 506–518.
Lahti JM, Xiang JL, Heath LS, Campana D and Kidd VJ. . 1995 Mol. Cell. Biol. 15: 1–11.
Levkau B, Koyama H, Raines EW, Clurman BE, Herren B, Orth K, Roberts JM and Ross R. . 1998 Mol. Cell. 1: 553–563.
Loubat A, Rochet N, Turchi L, Rezzonico R, Far DF, Auberger P, Rossi B and Ponzio G. . 1999 Oncogene 18: 3324–3333.
Luo Y, Marx SO, Kiyokawa H, Koff A, Massague J and Marks A. . 1996 Mol. Cell. Biol. 16: 6744–6751.
Meikrantz W, Gisselbrecht S, Tam SW and Schlegel R. . 1994 Proc. Natl. Acad. Sci. USA 91: 3754–3758.
Menézes J, Leibold W, Klein G and Clements G. . 1975 Biomedicine 22: 276–284.
Morley SJ, McKendrick L and Bushell M. . 1998 FEBS Lett. 438: 41–48.
Nourse J, Firpo E, Flanagan WM, Coats S, Polyak K, Lee MH, Massague J, Crabtree GR and Roberts JM. . 1994 Nature 372: 570–573.
Park JA, Kim K-W, Kim SI and Lee SK. . 1998 Eur. J. Biochem. 257: 242–248.
Peter ME and Krammer PH. . 1998 Curr. Opin. Immun. 10: 545–551.
Pochampally R, Fodera B, Chen L, Shao W, Levine EA and Chen J. . 1998 Oncogene 17: 2629–2636.
Polyak K, Kato JY, Solomon MJ, Sherr CJ, Massague J, Roberts JM and Koff A. . 1994a Genes Dev. 8: 9–22.
Polyak K, Lee MH, Erdjumentbromage H, Koff A, Roberts JM, Tempst P and Massague J. . 1994b Cell 78: 59–66.
Schreiber M, Muller WJ, Singh G and Graham FL. . 1999 Oncogene 18: 1663–1676.
Schulze-Osthoff K, Ferrari D, Los M, Wesselborg S and Peter ME. . 1998 Eur. J. Biochem. 254: 439–459.
Sherr CJ and Roberts JM. . 1999 Genes Dev. 13: 1501–1512.
Shi L, Nishioka WK, Thng J, Bradbury EM, Litchfield DW and Greenberg AH. . 1994 Science 263: 1143–1145.
Shimizu T, O'Connor PM, Kohn KW and Pommier Y. . 1995 Cancer Res. 55: 228–231.
Sinclair AJ, Palmero I, Peters G and Farrell PJ. . 1994 EMBO J. 13: 3321–3328.
Tan X, Martin SJ, Green DR and Wang JYJ. . 1997 J. Biol. Chem. 272: 9613–9616.
Toyoshima H and Hunter T. . 1994 Cell 78: 67–74.
Wang XT, Gorospe M, Huang Y and Holbrook NJ. . 1997 Oncogene 15: 2991–2997.
Zhang Y, Fujita N and Tsuruo T. . 1999 Oncogene 18: 1131–1138.
Acknowledgements
We would like to thank J Blenis and P Juo for generously providing the Jurkat A3 and Jurkat 9.2 cell lines. We are grateful to S Morley for helpful discussions during the course of this work. This work was funded by grants from the Leukaemia Research Fund and the Wellcome Trust.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Frost, V., Sinclair, A. p27KIP1 is down-regulated by two different mechanisms in human lymphoid cells undergoing apoptosis. Oncogene 19, 3115–3120 (2000). https://doi.org/10.1038/sj.onc.1203657
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1203657
Keywords
This article is cited by
-
Pro-apoptotic properties of hyperforin in leukemic cells from patients with B-cell chronic lymphocytic leukemia
Leukemia (2006)
-
Flavopiridol downregulates the expression of both the inducible NO synthase and p27kip1 in malignant cells from B-cell chronic lymphocytic leukemia
Leukemia (2003)
-
Exploitation of a non-apoptotic caspase to regulate the abundance of the cdkI p27KIP1 in transformed lymphoid cells
Oncogene (2001)