TGF- beta sub(1) induces the cyclin-dependent kinase inhibitor p27 super(Kip1) mRNA and protein in murine B cells

• Published in: The Journal of immunology (1950) 1998-01, Vol.160 (2), p.770-777
• Main Authors: Kamesaki, H, Nishizawa, K, Michaud, G Y, Cossman, J, Kiyono, T
• Format: Article
• Language: English
• ISSN: 0022-1767

TGF- beta sub(1) inhibits the cell cycle progression of many types of cells by arresting them in the G sub(1) phase. This cell cycle arrest has been attributed to the regulatory effects of TGF- beta sub(1) on both the levels and the activities of the G sub(1) cyclins and their kinase partners. The activities of these kinases are negatively regulated by a number of proteins, such as p15 super(INK4b), p21 super(WAF1/Cip1), and p27 super(Kip1), that physically associate with cyclins, cyclin-dependent kinases (Cdk), or cyclin-Cdk complexes. In epithelial cell lines, TGF- beta sub(1) was previously shown to inhibit cell cycle progression through down-regulation of Cdk4 and/or up-regulation of p15 super(INK4b) and/or p21 super(WAF1/Cip1). However, TGF- beta sub(1) had little or no effect on the p27 super(Kip1) mRNA and protein levels. In this report, we show that, in contrast to observations in epithelial cell lines, TGF- beta sub(1) increased the p27 super(Kip1) mRNA and protein levels in the murine B cell lines CH31 and WEHI231. This TGF- beta sub(1)-mediated induction of p27 super(Kip1) also resulted in an increased association of p27 super(Kip1) with Cdk2 and a decreased Cdk2 kinase activity. In contrast to epithelial cells, however, TGF- beta sub(1) had little or no effect on the Cdk4 and p21 super(WAF1/Cip1) protein levels in these B cells. Finally, although several studies suggested a direct role of p53 in TGF- beta sub(1)-mediated cell cycle arrest in epithelial cells, TGF- beta sub(1) inhibited cell cycle progression in CH31 even in the absence of wild-type p53. Taken together, these results suggest that TGF- beta sub(1) induces G sub(1) arrest in B cells primarily through a p53-independent up-regulation of p27 super(Kip1) protein.