Stat proteins control lymphocyte proliferation by regulating p27(Kip1) expression

Mark H. Kaplan, Carla Daniel, Ulrike Schindler, Michael J. Grusby

Research output: Contribution to journalArticle

111 Scopus citations

Abstract

The proliferation of lymphocytes in response to cytokine stimulation is essential for a variety of immune responses. Recent studies with signal transducer and activator of transcription 6 (Stat6)-deficient mice have demonstrated that this protein is required for the normal proliferation of lymphocytes in response to interleukin-4 (IL-4). In this report, we show that the impaired IL-4-induced proliferative response of Stat6-deficient lymphocytes is not due to an inability to activate alternate signaling pathways, such as those involving insulin receptor substrates, or to a failure to upregulate IL-4 receptor levels. Cell cycle analysis showed that the percentage of Stat6-deficient lymphocytes that transmit from the G1 to the S phase of the cell cycle following IL-4 stimulation is lower than that of control lymphocytes. Although the regulation of many genes involved in the control of cytokine-induced proliferation is normal in Stat6-deficient lymphocytes, protein levels of the cdk inhibitor p27(Kip1) were found to be markedly dysregulated. p27(Kip1) is expressed at significantly higher levels in Stat6-deficient lymphocytes than in control cells following IL-4 stimulation. The higher level of p27(Kip1) expression seen in IL-4-stimulated Stat6-deficient lymphocytes correlates with decreased Cdk2-associated kinase activity and is the result of the increased accumulation of protein rather than altered mRNA expression. Similarly, higher levels of p27(Kip1) protein expression are also seen following IL-12 stimulation of Stat4-deficient lymphocytes than are seen following stimulation of control cells. These data suggest that Stat proteins may control the cytokine-induced proliferative response of activated T cells by regulating the expression of cell cycle inhibitors so that cytokine-cdk complexes may function to promote transition from the G1 to the S phase of the cell cycle.

Original languageEnglish (US)
Pages (from-to)1996-2003
Number of pages8
JournalMolecular and cellular biology
Volume18
Issue number4
DOIs
StatePublished - Apr 1998

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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