Abstract
Expression of the cyclin dependent kinase inhibitor p27KIP1 is intimately linked to the control of proliferation, and is itself regulated by transcription, translation, phosphorylation, protein stability or sequestration. p27KIP1 is also regulated during apoptosis; cleavage occurs at DPSD139S and ESQD108V, by a sub-set of Z-VAD-fmk-sensitive caspases. We have identified a related but distinct mechanism that regulates p27KIP1 in proliferating lymphoid cell lines. In a B-lymphoid cell line (BJAB), the abundance of p27KIP1 oscillates inversely to proliferation; loss of full-length p27KIP1 correlates with the appearance of a truncated version corresponding to cleavage at DPSD139S. A direct correlation exists between the appearance of truncated p27KIP1 and the presence of an activity able to cleave peptides representing DPSD139S and a caspase-8 substrate (Ac-IETD-AMC) in vitro. This activity is inhibited by Ac-IETD-CHO but not Z-VAD-fmk in vitro. Furthermore a requirement for caspase-8 has been excluded. The activity differs from the apoptosis related p27KIP1-cleaving activity; indeed few cells undergoing apoptosis are present in the population of proliferating cells. The activity is further distinguished by its inability to cleave a peptide based on ESQD108V in vitro, together with the lack of a corresponding cleavage product in vivo. Inhibition of the caspase activity in vivo promotes an accumulation of full length p27KIP1, as well as a decrease in cell proliferation. Together these studies highlight the importance of non-apoptotic caspases in regulating p27KIP1 in transformed lymphoid cells.
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References
Agrawal D, Hauser P, McPherson F, Dong F, Garcia A, Pledger WJ . 1996 Mol. Cell. Biol. 16: 4327–4336
Akita K, Ohtsuki T, Nukada Y, Tanimoto T, Namba N, Okura T, Takakura-Yamamoto R, Torigoe K, Gu Y, Su MSS, Mufii M, Satoh-Itoh M, Yamamoto K, Kohno K, Ikeda M, Kurimoto M . 1997 J. Biol. Chem. 272: 26595–26603
Alam A, Cohen LY, Aouad S, Sekaly R-P . 1999 J. Exp. Med. 190: 1879–1890
Barnouin K, Fredersdorf S, Eddaoudi A, Mittnacht S, Pan LX, Du MQ, Lu X . 1999 Oncogene 18: 6388–6397
Cannell EJ, Farrell PJ, Sinclair AJ . 1996 Oncogene 13: 1413–1421
Cannell EJ, Farrell PJ, Sinclair AJ . 1998 FEBS Lett. 439: 297–301
Catzavelos C, Bhatacharya N, Ung YC, Wilson JA, Roncari L, Sandhu C, Shaw P, Yeger H, Morava-Protzner I, Kapusta L, Franssen E, Pritchard KI, Slingerland JM . 1997 Nature Med. 3: 227–230
Chen L, Marechal V, Moreau J, Levine AJ, Chen J . 1997 J. Biol. Chem. 272: 22966–22973
Clements GB, Klein G, Povey S . 1975 Intl. J. Cancer 16: 125–133
Craig C, Wersto R, Kim M, Ohri E, Li ZW, Katayose D, Lee SJ, Trepel J, Cowan K, Seth P . 1997 Oncogene 14: 2283–2289
Ekert PG, Silke J, Vaux DL . 1999 Cell Death Different. 6: 1081–1086
Erhardt P, Tomaselli KJ, Cooper GM . 1997 J. Biol. Chem. 272: 15049–15052
Eymin B, Haugg M, Droin N, Sordet O, Dimanche-Boitrel M-T, Solary E . 1999a Oncogene 18: 1411–1418
Eymin B, Sordet O, Droin N, Munsch B, Haugg M, Van de Craen M, Vandenabeele P, Solary E . 1999b Oncogene 18: 4839–4847
Fero ML, Randel E, Gurley KE, Roberts JM, Kemp CJ . 1998 Nature 396: 177–180
Fredersdorf S, Burns J, Milne AM, Packham G, Fallis L, Gillett CE, Royds JA, Peston D, Hall PA, Hanby AM, Barnes DM, Shousha S, Ohare MJ, Lu X . 1997 Proc. Natl. Acad. Sci. USA 94: 6380–6385
Frost V, Sinclair AJ . 2000 Oncogene 19: 3115–3120
Garcia-Calvo M, Peterson EP, Leiting B, Ruel R, Nicholson DW, Thornberry NA . 1998 J. Biol. Chem. 273: 32608–32613
Harvey KJ, Lukovic D, Ucker DS . 2000 J. Cell Biol. 148: 59–72
Hengst L, Reed SI . 1996 Science 271: 1861–1864
Hiromura K, Pippin JW, Fero ML, Roberts JM, Shankland SJ . 1999 J. Clin. Invest. 103: 597–604
Juo P, Kuo CJ, Yuan J, Blenis J . 1998 Curr. Biol. 8: 1001–1008
Kawamata S, Sakaida H, Hori T, Maeda M, Uchiyama T . 1998 Blood 91: 561–569
Kennedy NJ, Kataoka T, Tschopp J, Budd RC . 1999 J. Exper. Med. 190: 1891–1895
Kiyokawa H, Kineman RD, ManovaTodorova KO, Soares VC, Hoffman ES, Ono M, Khanam D, Hayday AC, Frohman LA, Koff A . 1996 Cell 85: 721–732
Kwon TK, Buchholz MA, Ponsalle P, Chrest FJ, Nordin AA . 1997 J. Immunol. 158: 5642–5648
Kwon TK, Nagel JE, Buchholz MA, Nordin AA . 1996 Gene 180: 113–120
Levkau B, Koyama H, Raines EW, Clurman BE, Herren B, Orth K, Roberts JM, Ross R . 1998 Mol. Cell 1: 553–563
Loda M, Cukor B, Tam SW, Lavin P, Fiorentino M, Draetta GF, Jessup JM, Pagano M . 1997 Nature Med. 3: 231–234
Loubat A, Rochet N, Turchi L, Rezzonico R, Far DF, Auberger P, Rossi B, Ponzio G . 1999 Oncogene 18: 3324–3333
Luo Y, Marx SO, Kiyokawa H, Koff A, Massague J, Marks A . 1996 Mol. Cell. Biol. 16: 6744–6751
Millard SS, Yan JS, Nguyen HA, Pagano M, Kiyokawa H, Koff A . 1997 J. Biol. Chem. 272: 7093–7098
Miossec C, Dutilleul V, Fassy F, Die-Hercend A . 1997 J. Biol. Chem. 272: 13459–13462
Mittnacht S . 1998 Curr. Opin. Gene. Dev. 8: 21–27
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. Biophy. Res. Comm. 240: 386–390
Nakayama K, Ishida N, Shirane M, Inomata A, Inoue T, Shishido N, Hori I, Loh DY . 1996 Cell 85: 707–720
Nguyen H, Gitig DM, Koff A . 1999 Mol. Cell. Biol. 19: 1190–1201
Nicholson DW . 1999 Cell Death Differ. 6: 1028–1042
Nourse J, Firpo E, Flanagan WM, Coats S, Polyak K, Lee MH, Massague J, Crabtree GR, Roberts JM . 1994 Nature 372: 570–573
Pagano M, Tam SW, Theodoras AM, Beerromero P, Delsal G, Chau V, Yew PR, Draetta GF, Rolfe M . 1995 Science 269: 682–685
Park DS, Morris EJ, Padmanabhan J, Shelanski ML, Geller HM, Greene LA . 1998 J. Cell Biol. 143: 457–467
Pochampally R, Fodera B, Chen L, Lu W, Chen J . 1999 J. Biol. Chem. 274: 15271–15277
Pochampally R, Fodera B, Chen L, Shao W, Levine EA, Chen J . 1998 Oncogene 17: 2629–2636
Polyak K, Kato JY, Solomon MJ, Sherr CJ, Massague J, Roberts JM, Koff A . 1994a Genes Dev. 8: 9–22
Polyak K, Lee MH, Erdjumentbromage H, Koff A, Roberts JM, Tempst P, Massague J . 1994b Cell 78: 59–66
Poon RYC, Toyoshima H, Hunter T . 1995 Mol. Biol. Cell 6: 1197–1213
Porter PL, Malone KE, Heagerty PJ, Alexander GM, Gatti LA, Firpo EJ, Daling JR, Roberts JM . 1997 Nature Med. 3: 222–225
Reynisdottir I, Polyak K, Iavarone A, Massague J . 1995 Genes Dev. 9: 1831–1845
Schreiber M, Muller WJ, Singh G, Graham FL . 1999 Oncogene 18: 1663–1676
Sheaff RJ, Groudine M, Gordon M, Roberts JM, Clurman BE . 1997 Genes Dev. 11: 1464–1478
Sherr CJ, Roberts JM . 1995 Genes Dev. 9: 1149–1163
Sherr CJ, Roberts JM . 1999 Genes Dev. 13: 1501–1512
Sinclair AJ, Palmero I, Peters G, Farrell PJ . 1994 EMBO J. 13: 3321–3328
Soos TJ, Kiyokawa H, Yan JS, Rubin MS, Giordano A, DeBlasio A, Bottega S, Wong BM, Mendelsohn J, Koff A . 1996 Cell Growth Differ. 7: 135–146
Spender LC, Cannell EJ, Hollyoake M, Wensing B, Gawn JM, Brimmell M, Packham G, Farrell PJ . 1999 J. Virol. 73: 4678–4688
Talanian RV, Quinlan C, Trautz S, Hackett MC, Mankovich JA, Banach D, Ghayur T, Brady KD, Wong WW . 1997 J. Biol. Chem. 272: 9677–9682
Thornberry NA, Rano TA, Peterson EP, Rasper DM, Timkey T, Garcia-Calvo M, Houtzager VM, Nordstrom PA, Roy S, Vaillancourt JP, Chapman KT, Nicholson DW . 1997 J. Biol. Chem. 272: 17907–17911
Toyoshima H, Hunter T . 1994 Cell 78: 67–74
Vlach J, Hennecke S, Alevizopoulos K, Conti D, Amati B . 1996 EMBO J. 15: 6595–6604
Vlach J, Hennecke S, Amati B . 1997 EMBO J. 16: 5334–5344
Wang XT, Gorospe M, Huang Y, Holbrook NJ . 1997 Oncogene 15: 2991–2997
Wilhelm S, Wagner H, Hacker G . 1998 Eur. J. Immun. 28: 891–900
Wu DM, Zhang Y, Parada NA, Kornfield H, Nicoll J . 1999 J. Immun. 162: 1287–1293
Zeuner A, Eramo A, Peschle C, De Maria R . 1999 Cell Death Different. 6: 1075–1080
Zhang Y, Center DM, Wu DM, Cruikshank WW, Juan Y, Andrews DW, Kornfield H . 1998 J. Biol. Chem. 273: 1144–1149
Acknowledgements
We would like to thank J Blenis and P Juo for generously providing the Jurkat A3 and Jurkat 9.2 cell lines and J Massague for providing the human p27KIP1 cDNA. 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, the Wellcome Trust and the Medical Research Council.
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Frost, V., Al-Mehairi, S. & Sinclair, A. Exploitation of a non-apoptotic caspase to regulate the abundance of the cdkI p27KIP1 in transformed lymphoid cells. Oncogene 20, 2737–2748 (2001). https://doi.org/10.1038/sj.onc.1204367
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DOI: https://doi.org/10.1038/sj.onc.1204367
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