Visualizing the Dynamics of${\rm p}21^{{\rm Waf}1/{\rm Cip}1}$Cyclin-Dependent Kinase Inhibitor Expression in Living Animals

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 104; no. 38; pp. 15034 - 15039
• Main Authors: Ohtani, Naoko, Imamura, Yuko, Yamakoshi, Kimi, Hirota, Fumiko, Nakayama, Rika, Kubo, Yoshiaki, Ishimaru, Naozumi, Takahashi, Akiko, Hirao, Atsushi, Shimizu, Takatsune, Mann, David J., Saya, Hideyuki, Hayashi, Yoshio, Arase, Seiji, Matsumoto, Mitsuru, Nakao, Kazuki, Hara, Eiji
• Format: Journal Article
• Language: English
• Published: National Academy of Sciences 18.09.2007
• Subjects: Bioluminescence; Gene expression; Hair; Hair follicles; Imaging; Inductive reasoning; Mice; Papilloma; Skin; Transgenic animals
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0706949104

Although the role of$p21^{Waf1/Cip1}$gene expression is well documented in various cell culture studies, its in vivo roles are poorly understood. To gain further insight into the role of$p21^{Waf1/Cip1}$gene expression in vivo, we attempted to visualize the dynamics of$p21^{Waf1/Cip1}$gene expression in living animals. In this study, we established a transgenic mice line (p21-p-luc) expressing the firefly luciferase under the control of the$p21^{Waf1/Cip1}$gene promoter. In conjunction with a noninvasive bioluminescent imaging technique, p21-p-luc mice enabled us to monitor the endogenous$p21^{Waf1/Cip1}$gene expression in vivo. By monitoring and quantifying the$p21^{Waf1/Cip1}$gene expression repeatedly in the same mouse throughout its entire lifespan, we were able to unveil the dynamics of$p21^{Waf1/Cip1}$gene expression in the aging process. We also applied this system to chemically induced skin carcinogenesis and found that the levels of$p21^{Waf1/Cip1}$gene expression rise dramatically in benign skin papillomas, suggesting that$p21^{Waf1/Cip1}$plays a preventative role(s) in skin tumor formation. Surprisingly, moreover, we found that the level of$p21^{Waf1/Cip1}$expression strikingly increased in the hair bulb and oscillated with a 3-week period correlating with hair follicle cycle progression. Notably, this was accompanied by the expression of p63 but not p53. This approach, together with the analysis of$p21^{Waf1/Cip1}$knockout mice, has uncovered a novel role for the$p21^{Waf1/Cip1}$gene in hair development. These data illustrate the unique utility of bioluminescence imaging in advancing our understanding of the timing and, hence, likely roles of specific gene expression in higher eukaryotes.