Sonic hedgehog opposes epithelial cell cycle arrest

Stratified epithelium displays an equilibrium between proliferation and cel l cycle arrest, a balance that is disrupted in basal cell carcinoma (BCC). Sonic hedgehog (Shh) pathway activation appears sufficient to induce BCC, h owever, the way it does so is unknown. Shh-induced epidermal hyperplasia is accompanied by continued cell proliferation in normally growth arrested su prabasal cells in vivo. Shh-expressing cells fail to exit S and G2/M phases in response to calcium- induced differentiation and also resist exhaustion of replicative growth capacity. In addition, Shh blocks p21(CIP1/WAF1)-ind uced growth arrest. These data indicate that Shh promotes neoplasia by oppo sing normal stimuli for epithelial cell cycle arrest.