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  • Original Paper
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Molecular mechanisms underlying interferon-α-induced G0/G1 arrest: CKI-mediated regulation of G1 Cdk-complexes and activation of pocket proteins

Abstract

One prominent effect of IFNs is their cell growth-inhibitory activity. The mechanism behind this inhibition of proliferation is still not fully understood. In this study, the effect of IFN-α treatment on cell cycle progression has been analysed in three lymphoid cell lines, Daudi, U-266 and H9. Examination of the growth-arrested cell populations shows that Daudi cells accumulate in a G0-like state, whereas U-266 cells arrest later in G1. H9 cells are completely resistant to IFN-α's cell growth-inhibitory effects. The G0/G1-phase arrest is preceded by a rapid induction of the cyclin-dependent kinase inhibitors (CKIs), p21 and p15. In parallel, the activities of the G1 Cdks are significantly reduced. In addition to p21/p15 induction, IFN-α regulates the expression of another CKI, p27, presumably by a post-transcriptional mechanism. In the G1 Cdk-complexes, there is first an increased binding of p21 and p15 to their respective kinases. At longer exposure times, when Cdk-bound p15 and p21 decline, p27 starts to accumulate. Furthermore, we found that IFN-α not only suppresses the phosphorylation of pRb, but also alters the phosphorylation and expression of the other pocket proteins p130 and p107. These data suggest that induction of p21/p15 is involved in the primary IFN-α response inhibiting G1 Cdk activity, whereas increased p27 expression is part of a second set of events which keep these Cdks in their inactive form. Moreover, elevated levels of p27 correlated with a dissociation of cyclin E/Cdk2-p130 or p107 complexes to yield cyclin E/Cdk2-p27 complexes. In resistant H9 cells, which possess a homozygous deletion of the p15/p16 genes and lack p21 protein expression, IFN-α causes no detectable changes in p27 expression and, furthermore, no effects are observed on either pocket proteins in this cell line. Taken together, these data suggest that the early decline in G1 Cdk activity, subsequent changes in phosphorylation of pocket proteins, and G1/G0 arrest following IFN-α treatment, is not primarily due to loss of the G1 kinase components, but result from the inhibitory action of CKIs on these complexes.

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References

  • Aprelikova O, Xiong Y and Liu ET. . 1995 J. Biol. Chem. 270: 18195–18197.

  • Borgonovo Brandter L, Heyman M, Rasool O, Liu Y, Grandér D and Einhorn S. . 1996 Eur. J. Haematol. 56: 313–318.

  • Brenning G, Åhre A and Nilsson K. . 1985 Scand. J. Haematol. 35: 543–549.

  • Clurman BE, Sheaff RJ, Thress K, Groudine M and Roberts JM. . 1996 Genes Dev. 10: 1979–1990.

  • Corradini P, Inghiarami G, Astolfi M, Ladetto M, Voena C, Ballerini P, Gu W, Nilsson K, Knowles DM, Boccadoro M, Pileri A and Della-Favera R. . 1994 Leukemia 8: 758–767.

  • Datto MB, Li Y, Panus JF, Howe DJ, Xiong Y and Wang XF. . 1995 Proc. Natl. Acad. Sci. USA 92: 5545–5549.

  • De Mayer E and De Mayer-Guiginard J. . (1988) In: Interferons and other regulatory cytokines. John Wiley & Sons Inc: New York, NY.

    Google Scholar 

  • Dimri GP, Nakanishi M, Desprez PY, Smith JR and Campisi J. . 1996 Mol. Cell. Biol. 16: 2987–2997.

  • El-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.

  • Erickson S, Sangfelt O, Heyman M, Einhorn S, Castro J and Grandér D. . 1998 Oncogene 17: 595–602.

  • Gerdes J, Lemke H, Baisch H, Wacker HH, Schwab U and Stein H. . 1984 J. Immunol. 133: 1710–1715.

  • Grandér D, Sangfelt O and Erickson S. . 1997 Eur. J. Hamatol. 59: 129–135.

  • Gu Y, Rosenblatt J and Morgan DO. . 1992 EMBO J. 11: 3995–4005.

  • Hall M, Bates S and Peters G. . 1995 Oncogene 11: 1581–1588.

  • Hannon GJ and Beach D. . 1994 Nature 371: 257–261.

  • Hengst L, Dulic V, Slingerland JM, Lees E and Reed SI. . 1994 Proc. Natl. Acad. Sci. USA 91: 5291–5295.

  • Hengst L and Reed SI. . 1996 Science 271: 1861–1864.

  • Heiden T, Gohde W and Tribukait B. . 1990 Anticancer Res. 10: 1555–1562.

  • Kaczmarek L. . 1986 Lab. Invest. 54: 365–376.

  • Kato J, Matsuoka M, Polyak K, Massagué J and Sherr CJ. . 1994 Cell 79: 487–496.

  • Kimchi A. . 1992 J. Cell. Biochem. 50: 1–9.

  • Kimchi A, Resnitzky D, Ber R and Gat G. . 1988 Mol. Cell. Biol. 8: 2828–2836.

  • Kranenburg O, Scharnhorst V, Van der Eb AJ and Zantema A. . 1995 J. Cell. Biol. 131: 227–234.

  • LaBaer J, Garrett MD, Stevenson LF, Slingerland JM, Sandhu C, Fattaey A and Harlow E. . 1997 Genes Dev. 11: 847–862.

  • Lee M, Williams B, Mulligan G, Mukai S, Bronson R, Dyson N, Harlow E and Jacks T. . 1996 Genes Dev. 10: 1621–1632.

  • Matsushime H, Quelle DE, Shurtleff SA, Shibuya M, Sherr CJ and Kato J-Y. . 1994 Mol. Cell. Biol. 14: 2066–2076.

  • Mayol X, Garriga J and Graña X. . 1996 Oncogene 13: 237–246.

  • Morgan DO. . 1995 Nature 374: 131–134.

  • Mulligan GJ, Wong J and Jacks T. . 1998 Mol. Cell. Biol. 18: 206–220.

  • Nicolescu III AB, Chen X, Smeets M, Hengst L, Prives C and Reed SI. . 1998 Mol. Cell. Biol. 18: 629–643.

  • Nourse J, Firpo E, Flanagan MW, Coats S, Polyak K, Lee M-H, Massagué J, Crabtree GR and Roberts JM. . 1994 Nature 372: 570–573.

  • Palmero I and Peters G. . 1996 Cancer Surv. 27: 351–367.

  • Parry D, Bates S, Mann DJ and Peters G. . 1995 EMBO J. 14: 503–511.

  • Pines J. . 1995 Biochem. J. 308: 687–711.

  • Polyak K, Kato JY, Solomon MJ, Sherr CJ, Massagué J, Roberts JM and Koff A. . 1994 Genes Dev. 8: 9–22.

  • Pokrovskaja K, Ehlin-Henriksson B, Bartkova J, Bartek J, Scuderi R, Szekely L, Wiman KG and Klein G. . 1996 Cell Growth Diff. 7: 1723–1732.

  • Reed SI, Bailly E, Dulic V, Hengst L, Resnitzky D and Slingerland J. . 1994 J. Cell Sci. Suppl. 18: 69–73.

  • Reynisdottír I and Massagué J. . 1997 Genes Dev. 11: 492–503.

  • Reynisdottír I, Polyak K, Ivarone A and Massagué J. . 1995 Genes Dev. 9: 1831–1845.

  • Sangfelt O, Erickson S, Castro J, Heiden T, Einhorn S and Grandér D. . 1997a Cell Growth Diff. 8: 343–352.

  • Sangfelt O, Erickson S, Einhorn S and Grandér D. . 1997b Oncogene 14: 415–423.

  • Shiyanov P, Bagchi S, Adami G, Kokontis J, Hay N, Arroyo M, Morozov A and Raychaudhuri P. . 1996 Mol. Cell. Biol. 16: 737–744.

  • Sherr CJ and Roberts JM. . 1995 Genes Dev. 9: 1149–1163.

  • Taylor-Papadimitriou J and Rozengurt E. . 1985 Interferons, their impact in biology and medicine. In J. Taylor-Papadimitriou (ed.). Oxford Medical Publications: Oxford. p81.

    Google Scholar 

  • Tiefenbrun N, Melamed D, Levy N, Resnitzky D, Hoffman I, Reed SI and Kimchi A. . 1996 Mol. Cell. Biol. 16: 3934–3944.

  • Vairo G, Livingston DM and Ginsberg D. . 1995 Genes Dev. 9: 869–881.

  • Vlach J, Hennecke S and Amati B. . 1997 EMBO J. 17: 5334–5344.

  • Weinberg RA. . 1995 Cell 81: 323–330.

  • Woo MS, Sánchez I and Dynlacht BD. . 1997 Mol. Cell. Biol. 17: 3566–3579.

  • Zhu L, Enders G, Lees JA, Beijersbergen RL, Bernards R and Harlow E. . 1995a EMBO J. 14: 1904–1913.

  • Zhu L, Harlow E and Dynlacht BD. . 1995b Genes Dev. 9: 1740–1752.

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Acknowledgements

The excellent technical assistance of Ms Ann-Charlotte Björklund and Elisabet Anderbring is gratefully acknowledged. We gratefully acknowledge the individuals who kindly provided antibodies and cDNA probes for these studies. We thank Drs Anders Zetterberg and Neil Portwood for helpful discussions and critical reading of the manuscript. This study was supported with grants from the Cancer Society of Stockholm, the Alex and Eva Wallström foundation, the Swedish Cancer Society and the Felix Mindus Fund for leukemia research.

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Sangfelt, O., Erickson, S., Castro, J. et al. Molecular mechanisms underlying interferon-α-induced G0/G1 arrest: CKI-mediated regulation of G1 Cdk-complexes and activation of pocket proteins. Oncogene 18, 2798–2810 (1999). https://doi.org/10.1038/sj.onc.1202609

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