AbstractWe previously demonstrated that type 1 astrocytes exhibited homotypic cell contact‐dependent inhibition of proliferation with increased expression of cyclin‐dependent kinase inhibitor p27Kip1. Here, we investigated the functional role of p27 in contact‐dependent inhibition of astrocytes and reactive gliosis in vitro and in vivo. An increase in the number of proliferating cells was detected in high‐density cultures of astrocytes derived from mice carrying a targeted deletion in the p27 gene compared to astrocytes from wild‐type mice. Overexpression of p27 by adenovirus vectors inhibited astrocyte proliferation, which was accompanied by downregulation of cyclin A. In a gliosis model in vitro, a transient decrease in the p27 level and an increase in the proliferation rate were observed. Astrocyte proliferation following cortical injury lasted longer in p27‐deficient mice than in wild‐type mice. Forced expression of p27 in both in vitro and in vivo models of gliosis effectively suppressed astrocyte proliferation. In summary, we demonstrated that p27 contributed to the cell contact‐dependent inhibition of astrocyte proliferation and to the cessation of proliferation in reactive astrocytosis. p27 may be used to modulate reactive astrocytosis. GLIA 37:93–104, 2002. © 2002 Wiley‐Liss, Inc.