Abstract
Human T-cells immortalized (interleukin-2 [IL-2] dependent) by the human T-cell lymphotropic/leukemia virus type I (HTLV-I), in time, become transformed (IL-2 independent). To understand the biochemical basis of this transition, we have used the sibling HTLV-I-infected T-cell lines, N1186 (IL-2 dependent) and N1186-94 (IL-2 independent), as models to assess the responses to antiproliferative signals. In N1186 cells arrested in G1 after serum/interleukin-2 (IL-2) deprivation, downregulation of the cyclin E-CDK2 kinase activity correlated with decreased phosphorylation of CDK2 and accumulation of p27Kip1 bound to the cyclin E-CDK2 complex, as seen in normal activated PBMCs (peripheral blood mononuclear cells). In contrast, N1186-94 cells failed to arrest in G1 upon serum starvation, displayed constitutive cyclin E-associated kinase activity, and, although CDK2 was partially dephosphorylated, the amount of p27Kip1 bound to the complex did not increase. This observation, extended to two other IL-2-dependent as well as to three IL-2-independent HTLV-I-infected T-cell lines, suggests that the lack of cyclin E-CDK2 kinase downregulation found in the late phase of HTLV-I transformation may correlate with insufficient amounts of p27Kip1 associated with the cyclin E-CDK2 complex. Reconstitution experiments demonstrated that the addition of p27Kip1 to lysates from N1186-94 starved cells resulted in the downregulation of cyclin E-associated kinase activity supporting the notion that the unresponsiveness of the cyclin E-CDK2 complex to growth inhibitory signals may be due to inadequate amounts of p27Kip1 assembled with the complex in HTLV-I-transformed T-cells. In fact, the amount of p27Kip1 protein was lower in most HTLV-I-transformed (IL-2-independent) than in the immortalized (IL-2-dependent) HTLV-I-infected T-cells. Furthermore, specific inhibitors of the phosphatidylinositol 3-kinase (PI3K) induced an increase of p27Kip1 protein levels, which correlated with G1 arrest, in both IL-2-dependent and IL-2-independent HTLV-I-infected T-cells. Altogether, these results suggest that maintaining a low level of expression of p27Kip1 is a key event in HTLV-I transformation.
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References
Akagi T, Ono H and Shimotohno K. . 1996 Oncogene 12: 1645–1652.
Brennan P, Babbage JW, Burgering BMT, Groner B, Reif K and Cantrell DA. . 1997 Immunity 7: 679–689.
Cereseto A, Berneman Z, Koralnik I, Vaughn J, Franchini G and Klotman ME. . 1997 Leukemia 11: 866–870.
Cereseto A, Diella F, Mulloy JC, Cara A, Michieli P, Grassman R, Franchini G and Klotman ME. . 1996 Blood 88: 1551–1560.
Coats S, Flanagan WM, Nourse J and Roberts JM. . 1996 Science 272: 877–880.
Dumont FJ and Su Q. . 1995 Life Sci. 58: 373–395.
EI Deiry WS, Tokino T, Velculescu VE, Levy DB, Parsons R, Trent JM, Lin D, Mercer WE, Kinzler KW and Vogelstein B. . 1993 Cell 75: 817–825.
Fero ML, Rivkin M, Tasch M, Porter P, Carow CE, Firpo E, Polyak K, Tsai L-H, Broudy V, Perlmutter RM, Kaushansky K and Roberts JM. . 1996 Cell 85: 733–744.
Firpo EJ, Koff A, Solomon MJ and Roberts JM. . 1994 Mol. Cell. Biol. 14: 4889–4901.
Franchini G. . 1995 Blood 86: 3619–3639.
Gong J, Ardelt B, Traganos F and Darzynkiewicz Z. . 1994 Cancer Res. 54: 4285–4288.
Gu Y, Rosenblatt J and Morgan DO. . 1992 EMBO J. 11: 3995–4005.
Harper JW, Adami GR, Wei N, Keyomarsi K and Elledge SJ. . 1993 Cell 75: 805–816.
Johnson D, Frame MC and Wyke JA. . 1998 Oncogene 16: 2017–2028.
Keyomarsi K and Pardee AB. . 1993 Proc. Natl. Acad. Sci. USA 90: 1112–1116.
Keyomarsi K, O'Leary N, Molnar G, Lees E, Fingert HL and Pardee AB. . 1994 Cancer Res. 54: 380–385.
Kiyokawa H, Kineman RD, Manova-Todorova KO, Soares VC, Hoffman ES, Ono M, Khanam D, Hayday AC, Frohman LA and Koff A. . 1996 Cell 85: 721–732.
Koff A, Giordano A, Desai D, Yamashita K, Harper JW, Elledge S, Nashimoto T, Morgan DO, Franza BR and Roberts JM. . 1992 Science 257: 1959–1964.
Koff A, Ohtsuki M, Polyak K, Roberts JM and Massague J. . 1993 Science 260: 536–539.
La Baer J, Garret MD, Stevenson LF, Slingerland JM, Sandhu C, Chou HS, Fattaey A and Harlow E. . 1997 Genes Dev. 11: 847–862.
Leach FS, Elledge SJ, Sherr CJ, Willson JKV, Markowitz S, Kinzler KW and Vogelstein B. . 1993 Cancer Res. 53: 1986–1989.
Liu Y, Martindale JL, Gorospe M and Holbrook NJ. . 1996 Cancer Res. 56: 31–35.
Macleod KF, Sherry N, Hannon G, Beach D, Tokino T, Kinzler K, Vogelstein B and Jacks T. . 1995 Genes Dev. 9: 935–944.
Mantel C, Luo Z, Canfield J, Braun S, Deng C and Broxmeyer HE. . 1996 Blood 88: 3710–3719.
Markham PD, Salahuddin SZ, Kalyanaraman VS, Popovic M, Sarin P and Gallo RC. . 1983 Int. J. Cancer 31: 413–420.
Migone T-S, Lin JX, Cereseto A, Mulloy JC, O'Shea JJ, Franchini G and Leonard WJ. . 1995 Science 269: 79–81.
Migone T-S, Cacalano NA, Taylor N, Yi T, Waldmann TA and Johnston JA. . 1998 Proc. Natl. Acad. Sci. USA 95: 3845–3850.
Miyoshi I, Kubonishi I, Yoshimoto S, Akagi T, Ohtsuki Y, Shiraishi Y, Nagata K and Hinuma Y. . 1981 Nature 294: 770–771.
Morgan DO. . 1995 Nature 374: 131–134.
Mulloy JC, Migone T-S, Ross TM, Ton N, Green PL, Leonard WJ and Franchini G. . 1998 J. Virol. 72: 4408–4412.
Nakayama K, Ishida N, Shirane M, Inomata A, Inoue T, Shishido N, Horii I, Loh DY and Nakayama K-I. . 1996 Cell 85: 707–720.
Nourse J, Firpo E, Flanagan WM, Coats S, Polyak K, Lee M-H, Massague J, Crabtree GR and Roberts JM. . 1994 Nature 372: 570–573.
Pagano M, Tam SW, Theodoras AM, Beer-Romero P, Del Sal G, Chau V, Yew PR, Draetta GF and Rolfe M. . 1995 Science 269: 682–685.
Polyak K, Lee M-H, Erdjument-Bromage H, Koff A, Roberts JM, Tempst P and Massague' J. . 1994 Cell 78: 59–66.
Popovic M, Lange-Wantzin G, Sarin PS, Mann D and Gallo RC. . 1983 Proc. Natl. Acad. Sci. USA 80: 5402–5406.
Sheaff RJ, Groudine M, Gordon M, Roberts JM and Clurman BE. . 1997 Genes Dev. 11: 1464–1478.
Takemoto S, Mulloy JC, Cereseto A, Migone T-S, Patel BKR, Matsuoka M, Yamaguchi K, Takatsuki K, Kamihira S, White JD, Leonard W, Waldmann T and Franchini G. . 1997 Proc. Natl. Acad. Sci. USA 94: 13897–13902.
Toyoshima H and Hunter T. . 1994 Cell 78: 67–74.
Vlach J, Hennecke S and Amati B. . 1997 EMBO J. 16: 5334–5344.
Xu X, Kang SH, Heidenreich O, Okerholm M, O'Shea JJ and Nerenberg MI. . 1995 J. Clin. Invest. 96: 1548–1555.
Zetterberg A, Larsson O and Wiman KG. . 1995 Curr. Opin. Cell. Biol. 7: 835–842.
Zhang H, Hannon J and Beach D. . 1994 Genes Dev. 8: 1750–1758.
Acknowledgements
We thank Drs A Cara and JC Mulloy for helpful discussion and Kelli Carrington, Steven Snodgrass, and Sydnye White for editorial assistance.
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Cereseto, A., Parks, R., Rivadeneira, E. et al. Limiting amounts of p27Kip1 correlates with constitutive activation of cyclin E-CDK2 complex in HTLV-I-transformed T-cells. Oncogene 18, 2441–2450 (1999). https://doi.org/10.1038/sj.onc.1202567
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DOI: https://doi.org/10.1038/sj.onc.1202567
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