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Mol Cell Biol, April 1998, p. 1996-2003, Vol. 18, No. 4
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Stat Proteins Control Lymphocyte Proliferation by Regulating p27Kip1 Expression

Mark H. Kaplan,1,dagger Carla Daniel,2 Ulrike Schindler,2 and Michael J. Grusby1,3,*

Department of Immunology and Infectious Diseases, Harvard School of Public Health,1 and Department of Medicine, Harvard Medical School,3 Boston, Massachusetts 02115, and Tularik, Inc., South San Francisco, California 940802

Received 15 July 1997/Returned for modification 5 September 1997/Accepted 15 January 1998

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 transit 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 p27Kip1 were found to be markedly dysregulated. p27Kip1 is expressed at significantly higher levels in Stat6-deficient lymphocytes than in control cells following IL-4 stimulation. The higher level of p27Kip1 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 p27Kip1 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 cyclin-cdk complexes may function to promote transition from the G1 to the S phase of the cell cycle.

* Corresponding author. Mailing address: Harvard School of Public Health, Department of Immunology and Infectious Diseases, 651 Huntington Ave., Boston, MA 02115. Phone: (617) 432-1240. Fax: (617) 432-0084. E-mail: grusby{at}mbcrr.harvard.edu.

dagger Present address: Walther Oncology Center, Indianapolis, IN 46202.




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