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Induction of Cip/Kip and Ink4 cyclin dependent kinase inhibitors by interferon-α in hematopoietic cell lines

Abstract

One prominent effect of IFNs is their cell growth inhibitory activity. The exact molecular mechanism behind this inhibition of proliferation remains to be elucidated. Possible effectors for IFN-induced growth inhibition are the recently discovered cyclin-dependent kinase inhibitors. The effect of IFN-α treatment on the members of the Ink4 and Cip/Kip families of Cdk inhibitors was investigated in three hematopoietic cell lines Daudi, U-266 and H9. Two of these cell lines, Daudi and U-266, respond to IFN-α by G1 arrest, whereas the H9 cell line is not growth arrested by IFN-α. We show that a p53-independent upregulation of p21 mRNA occurs following IFN-α treatment in all three cell lines. In Daudi and U-266 cells, the mRNA induction is accompanied by an increase in p21 protein, followed by an increased binding of p21 to Cdk2 and a subsequent decrease in Cdk2 activity, temporally coinciding with G1 arrest. In both these cell lines, there was also an increased binding of p21 to Cdk4. In contrast, p21 protein was not expressed in H9 cells, despite high levels of p21 mRNA following IFN-α treatment. In U-266 cells, IFN-α increased not only p21 but also p15 mRNA and protein levels, followed by an increased association of p15 with Cdk4. Furthermore, IFN-α treatment caused a four- to sixfold induction of the p16 E1β transcript in U-266 cells. Expression levels of the other Ink4 and Cip/Kip Cdk inhibitors were not induced by IFN treatment in any of the cell lines. We conclude that IFN-α can act as a potent regulator of Cdk-inhibitor expression, correlating with decreased Cdk activity and cell growth inhibition. One mechanism for resistance to IFN may be loss of the ability of cells to upregulate these proteins.

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Correspondence to Dan Grandér.

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Sangfelt, O., Erickson, S., Einhorn, S. et al. Induction of Cip/Kip and Ink4 cyclin dependent kinase inhibitors by interferon-α in hematopoietic cell lines. Oncogene 14, 415–423 (1997). https://doi.org/10.1038/sj.onc.1200832

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Keywords

  • interferon
  • cell cycle
  • cyclin-dependent kinase
  • cyclin-dependent kinase inhibitors

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