Mol Cell Biol 18(4): 1996-2003

Stat Proteins Control Lymphocyte Proliferation by Regulating p27<sup>Kip1</sup> Expression

Department of Immunology and Infectious Diseases, Harvard School of Public Health,^{and Department of Medicine, Harvard Medical School,}^{Boston, Massachusetts 02115, and Tularik, Inc., South San Francisco, California 94080}²

^{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:}ude.dravrah.rrcbm@ybsurg.

^{Present address: Walther Oncology Center, Indianapolis, IN 46202.}

Received 1997 Jul 15; Revisions requested 1997 Sep 5; Accepted 1998 Jan 15.

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 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 p27^{were found to be markedly dysregulated. p27}^{is expressed at significantly higher levels in Stat6-deficient lymphocytes than in control cells following IL-4 stimulation. The higher level of p27}^{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}^{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 G}₁ to the S phase of the cell cycle.

Abstract

The proliferation of lymphocytes is dependent on the receipt of appropriate signals to complete transitions through the cell cycle. Antigen activation of a T lymphocyte, mediated by cross-linking of T-cell receptor complexes, enables the cell to transit from the G₀ to the G₁ phase of the cell cycle. Activated T lymphocytes then require cytokine stimulation to continue through the cell cycle and progress from the G₁ to the S phase (33). In the absence of this second signal, lymphocytes do not proliferate and will undergo apoptosis.

The proliferative response of lymphocytes to interleukin-4 (IL-4) provides a useful model system for studying the mechanisms regulating cytokine-induced proliferation. IL-4-mediated responses result from the interaction of a ligand with a cell surface receptor composed of at least two membrane proteins; one chain specific for interactions with IL-4 (IL-4Rα) and a second common chain (γc) also used by the receptors for IL-2, IL-7, IL-9, and IL-15 (16, 27, 40, 48, 56). Recent studies have shown that a subunit of the high-affinity IL-13 receptor (IL-13R) may also be involved in one form of the IL-4R (18). Engagement of the IL-4R leads to activation of at least two distinct signaling pathways. IL-4 stimulation activates Janus kinases Jak1 and Jak3 (20, 36). The subsequent phosphorylation of the IL-4Rα chain at specific tyrosine residues by Jak kinases results in the activation of Stat6 (19, 28, 50). IL-4R engagement has also been shown to induce the phosphorylation of insulin receptor substrate (IRS) molecules such as IRS-1 and 4PS or IRS-2 (23, 54). Activated IRS-2 associates with phosphatidylinositol 3-kinase and may be responsible for mediating some IL-4-induced responses. A portion of the Ras pathway is also activated in response to IL-4, although studies have shown that this signaling pathway does not contribute to the proliferative response induced by IL-4 in lymphocytes (45).

Analysis of the cytoplasmic portion of the IL-4Rα chain led to the suggestion that separate regions are responsible for activation of the Stat and IRS signaling pathways. The tyrosine at amino acid 497 (Y497, on the basis of a numbering system where 1 is the amino terminus of the mature IL-4R protein) of the human IL-4R is part of the IRS interaction site and has been shown to be crucial for IL-4-induced proliferation. Transfected IL-4Rs, truncated or mutated so that they do not contain Y497, do not support IL-4-induced proliferation (11, 23). Several other tyrosine-phosphorylated sites have been identified as Stat6 docking sites, and any one of them individually can mediate the activation of Stat6 (19, 49, 60). Transfected receptors containing Y497 but lacking the three Stat6 docking sites were able to convey a proliferative signal, leading to the initial conclusion that Stat6 is dispensable for IL-4-mediated proliferative responses (46). However, in later studies, Stat6 phosphorylation could be detected in these transfectants, and presumably occurs through the interaction of Stat6 with the IRS binding site (Y497) which has homology with Stat6 docking sites (49). If the IRS docking site is indeed capable of mediating Stat6 activation, it would not be possible to determine the relative roles of these two signaling pathways in the proliferative response by this approach.

To determine the role of Stat6 in mediating IL-4-induced responses, we and others have recently generated Stat6-deficient mice (21, 53, 55). These mice lack a normal proliferative response to IL-4 but not to other cytokines or polyclonal activators, strongly supporting a role for Stat6 in IL-4-induced proliferation. In this study, we investigate the molecular mechanism by which Stat molecules control cytokine-induced proliferation. We show that Stat proteins regulate p27^{expression and that modulation of p27}^{protein levels correlates with the ability of cytokine-stimulated cells to progress from the G}₁ to the S phase of the cell cycle.

ACKNOWLEDGMENTS

We thank L. Jackson-Grusby, M. Fero, J. Roberts, J. Pierce, M. White, and M. Gately for providing probes, antisera, and cytokines. We also thank M. Carroll for critical review of this paper.

M.H.K. is a Special Fellow and M.J.G. is a Scholar of the Leukemia Society of America. This work was supported by the Mathers Foundation and NIH grant AI40171.

ACKNOWLEDGMENTS

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