Abstract
Cellular differentiation frequently involves sequential peaks in the expression of cyclin-dependent kinase inhibitors (cdki's). For example, an increase in levels of the cdki p27Kip1 follows upregulation of p21Waf1 in several cell types induced to differentiate by diverse stimuli. In this study, we have investigated whether p21Waf1 expression itself, rather than the differentiating agent, could be increasing p27Kip1 protein levels. We used an inducible p21Waf1 expression vector in a K562 leukemic cell model which we had previously shown to initiate differentiation following p21Waf1 upregulation. The current study reports that p21Waf1 upregulated p27Kip1 protein without altering p27Kip1 mRNA levels. This effect did not depend on G1-phase arrest–the increase in p27Kip1 occurred at all phases of the cell cycle. p21Waf1-expressing extracts inhibited phosphorylation of p27Kip1 on threonine-187, leading to decreased ubiquitination and decreased proteasomal destruction of p27Kip1. In K562 cells, upregulation of p27Kip1 by p21Waf1 during differentiation facilitated an ordered transition between these two cdki's, each of which may distinctly influence the differentiation process.
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
Alessandrini A, Chiaur DS, Pagano M . 1997 Leukemia 11: 342–345
Baldassarre G, Belletti B, Bruni P, Boccia A, Trapasso F, Pentimalli F, Barone MV, Chiappetta G, Vento MT, Spiezia S, Fusco A, Viglietto G . 1999 J. Clin. Invest. 104: 865–874
Baldassarre G, Boccia A, Bruni P, Sandomenico C, Barone MV, Pepe S, Angrisano T, Belletti B, Motti ML, Fusco A, Viglietto G . 2000 Cell Growth Differ. 11: 517–526
Blain SW, Montalvo E, Massague J . 1997 J. Biol. Chem. 272: 25863–25872
Casini T, Pelicci PG . 1999 Oncogene 18: 3235–3243
Chen YJ, Lin JK, Lin-Shiau SY . 1999 Eur. J. Cell Biol. 78: 824–831
Coats S, Flanagan WM, Nourse J, Roberts JM . 1996 Science 272: 877–880
de Koning JP, Soede-Bobok AA, Ward AC, Schelen AM, Antonissen C, van Leeuwen D, Lowenberg B, Touw IP . 2000 Oncogene 19: 3290–3298
Di Cunto F, Topley G, Calautti E, Hsiao J, Ong L, Seth PK, Dotto GP . 1998 Science 280: 1069–1072
Estanyol JM, Jaumot M, Casanovas O, Rodriguez-Vilarrupla A, Agell N, Bachs O . 1999 J. Biol. Chem. 274: 33161–33165
Franklin DS, Xiong Y . 1996 Mol. Biol. Cell 7: 1587–1599
Ghiani CA, Eisen AM, Yuan X, DePinho RA, McBain CJ, Gallo V . 1999 Development 126: 1077–1090
Harvat BL, Wang A, Seth P, Jetten AM . 1998 J. Cell Sci. 111: 1185–1196
Hengst L, Reed SI . 1996 Science 271: 1861–1864
Hsieh FF, Barnett LA, Green WF, Freedman K, Matushansky I, Skoultchi AI, Kelley LL . 2000 Blood 96: 2746–2754
Huss R, Theis S, Deeg HJ . 1999 Br. J. Cancer 81: 808–813
Kawa S, Nikaido T, Aoki Y, Zhai Y, Kumagai T, Furihata K, Fujii S, Kiyosawa K . 1997 Br. J. Cancer 76: 884–889
Liu J, Estes ML, Drazba JA, Liu H, Prayson R, Kondo S, Jacobs BS, Barnett GH, Barna BP . 2000 Oncogene 19: 661–669
Mantel C, Luo Z, Canfield J, Braun S, Deng C, Broxmeyer HE . 1996 Blood 88: 3710–3719
Meng L, Mohan R, Kwok BH, Elofsson M, Sin N, Crews CM . 1999 Proc. Natl. Acad. Sci. USA 96: 10403–10408
Montagnoli A, Fiore F, Eytan E, Carrano AC, Draetta GF, Hershko A, Pagano M . 1999 Genes Dev. 13: 1181–1189
Morisaki H, Fujimoto A, Ando A, Nagata Y, Ikeda K, Nakanishi M . 1997 Biochem. Biophys. Res. Commun. 240: 386–390
Morrison RF, Farmer SR . 1999 J. Biol. Chem. 274: 17088–17097
Muller D, Bouchard C, Rudolph B, Steiner P, Stuckmann I, Saffrich R, Ansorge W, Huttner W, Eilers M . 1997 Oncogene 15: 2561–2576
Muto A, Kizaki M, Yamato K, Kawai Y, Kamata-Matsushita M, Ueno H, Ohguchi M, Nishihara T, Koeffler HP, Ikeda Y . 1999 Blood 93: 2225–2233
Nguyen H, Gitig DM, Koff A . 1999 Mol. Cell Biol. 19: 1190–1201
Orend G, Hunter T, Ruoslahti E . 1998 Oncogene 16: 2575–2583
Pagano M, Tam SW, Theodoras AM, Beer-Romero P, Del Sal G, Chau V, Yew PR, Draetta GF, Rolfe M . 1995 Science 269: 682–685
Panzenbock B, Bartunek P, Mapara MY, Zenke M . 1998 Blood 92: 3658–3668
Russo AA, Jeffrey PD, Patten AK, Massague J, Pavletich NP . 1996 Nature 382: 325–331
Sheaff RJ, Groudine M, Gordon M, Roberts JM, Clurman BE . 1997 Genes Dev. 11: 1464–1478
Snowden AW, Anderson LA, Webster GA, Perkins ND . 2000 Mol. Cell Biol. 20: 2676–2686
Soos TJ, Kiyokawa H, Yan JS, Rubin MS, Giordano A, DeBlasio A, Bottega S, Wong B, Mendelsohn J, Koff A . 1996 Cell Growth Differ. 7: 135–146
Steinman RA, Huang J, Yaroslavskiy B, Goff JP, Ball ED, Nguyen A . 1998 Blood 91: 4531–4542
Steinman RA, Yaroslavskiy BB, Kaplan S, Goff JG, Shields D . 2000 Leukemia Res. 24: 601–610
Tam SW, Theodoras AM, Pagano M . 1997 Leukemia 11: Suppl 3 363–366
Taniguchi T, Endo H, Chikatsu N, Uchimaru K, Asano S, Fujita T, Nakahata T, Motokura T . 1999 Blood 93: 4167–4178
Tian JQ, Quaroni A . 1999 Am. J. Physiol. 276: C1245–C1258
Tomoda K, Kubota Y, Kato J . 1999 Nature 398: 160–165
Tsutsui T, Hesabi B, Moons DS, Pandolfi PP, Hansel KS, Koff A, Kiyokawa H . 1999 Mol. Cell Biol. 19: 7011–7019
Urashima M, Teoh G, Chauhan D, Hoshi Y, Ogata A, Treon SP, Schlossman RL, Anderson KC . 1997 Blood 90: 279–289
Vairo G, Soos TJ, Upton TM, Zalvide J, DeCaprio JA, Ewen ME, Koff A, Adams JM . 2000 Mol. Cell Biol. 20: 4745–4753
Wagner EF, Hleb M, Hanna N, Sharma S . 1998 J. Immunol. 161: 1123–1131
Xu X, Nakano T, Wick S, Dubay M, Brizuela L . 1999 Biochemistry 38: 8713–8722
Yaroslavskiy B, Watkins S, Donnenberg AD, Patton TJ, Steinman RA . 1999 Blood 93: 2907–2917
Zi X, Agarwal R . 1999 Proc. Natl. Acad. Sci. USA 96: 7490–7495
Acknowledgements
We would like to thank Michael Meyer and Dr Albert Donnenberg for assistance with flow cytometry, and Dr Michele Pagano and Andrea Carrano for advice regarding nitrogen bomb usage. We also wish to thank Drs Candace Johnson, Robert Redner and Daniel Johnson for review of the manuscript. This work was supported in part by the Leukemia and Lymphoma Society of America Award 6111-99.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Steinman, R., Lu, Y., Yaroslavskiy, B. et al. Cell cycle-independent upregulation of p27Kip1 by p21Waf1 in K562 cells. Oncogene 20, 6524–6530 (2001). https://doi.org/10.1038/sj.onc.1204800
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1204800