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TGF-ß₁ Induces the Cyclin-Dependent Kinase Inhibitor p27^Kip1 mRNA and Protein in Murine B Cells

Hiroshi Kamesaki^*, Kimiko Nishizawa^*, Ginette Y. Michaud, Jeffrey Cossman and Tohru Kiyono

Laboratories of ^* Experimental Radiology and Viral Oncology, Aichi Cancer Center Research Institute, Chikusa-ku, Nagoya, Aichi, Japan; and Department of Pathology, Georgetown University, Washington, DC 20007

TGF-ß₁ inhibits the cell cycle progression of many types of cells by arresting them in the G₁ phase. This cell cycle arrest has been attributed to the regulatory effects of TGF-ß₁ on both the levels and the activities of the G₁ cyclins and their kinase partners. The activities of these kinases are negatively regulated by a number of proteins, such as p15^INK4b, p21^WAF1/Cip1, and p27^Kip1, that physically associate with cyclins, cyclin-dependent kinases (Cdk), or cyclin-Cdk complexes. In epithelial cell lines, TGF-ß₁ was previously shown to inhibit cell cycle progression through down-regulation of Cdk4 and/or up-regulation of p15^INK4b and/or p21^WAF1/Cip1. However, TGF-ß₁ had little or no effect on the p27^Kip1 mRNA and protein levels. In this report, we show that, in contrast to observations in epithelial cell lines, TGF-ß₁ increased the p27^Kip1 mRNA and protein levels in the murine B cell lines CH31 and WEHI231. This TGF-ß₁-mediated induction of p27^Kip1 also resulted in an increased association of p27^Kip1 with Cdk2 and a decreased Cdk2 kinase activity. In contrast to epithelial cells, however, TGF-ß₁ had little or no effect on the Cdk4 and p21^WAF1/Cip1 protein levels in these B cells. Finally, although several studies suggested a direct role of p53 in TGF-ß₁-mediated cell cycle arrest in epithelial cells, TGF-ß₁ inhibited cell cycle progression in CH31 even in the absence of wild-type p53. Taken together, these results suggest that TGF-ß₁ induces G₁ arrest in B cells primarily through a p53-independent up-regulation of p27^Kip1 protein.

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