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© The Rockefeller University Press, 0021-9525/2002/7/321 $5.00
The Journal of Cell Biology, Volume 158, Number 2, July 22, 2002 321-329

Cytoplasmic p21^Cip1/WAF1 regulates neurite remodeling by inhibiting Rho-kinase activity

¹ Department of Anatomy and Neuroscience, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan
² Department of Orthopedic Surgery, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan
³ CREST, Japan Science and Technology Corporation, Kawaguchi, Saitama 332-0012, Japan
⁴ Department of Pediatrics, Tokyo Medical and Dental University School of Medicine, Bunkyo-Ku, Tokyo 113-8519, Japan

Address correspondence to Toshihide Yamashita, Department of Anatomy and Neuroscience, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan. Tel.: 81-6-6879-3221. Fax: 81-6-6879-3229. E-mail: tyama{at}anat2.med.osaka-u.ac.jp

p21^Cip1/WAF1 has cell cycle inhibitory activity by binding to and inhibiting both cyclin/Cdk kinases and proliferating cell nuclear antigen. Here we show that p21^Cip1/WAF1 is induced in the cytoplasm during the course of differentiation of chick retinal precursor cells and N1E-115 cells. Ectopic expression of p21^Cip1/WAF1 lacking the nuclear localization signal in N1E-115 cells and NIH3T3 cells affects the formation of actin structures, characteristic of inactivation of Rho. p21^Cip1/WAF1 forms a complex with Rho-kinase and inhibits its activity in vitro and in vivo. Neurite outgrowth and branching from the hippocampal neurons are promoted if p21^Cip1/WAF1 is expressed abundantly in the cytoplasm. These results suggest that cytoplasmic p21^Cip1/WAF1 may contribute to the developmental process of the newborn neurons that extend axons and dendrites into target regions.

Key Words: p21^Cip1/WAF1; Rho-kinase; neurite outgrowth; differentiation; Rho

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