but very interesting that the negative regulation of the cell cycle that protects from HCC development relies exclusively on p21.
The promising idea behind the inactivation of p21 in Fah Ϫ/Ϫ mice was to reactivate apoptosis in order to first eliminate DNA-damaged hepatocytes followed by balanced liver regeneration, thus overcoming the consequences of HT1. However, the study of Willenbring et al. clearly demonstrates that the antiproliferative function of p21 is essential for preventing uncontrolled hepatocyte growth, whereas apoptosis alone is not sufficient to protect from liver carcinogenesis in HT1.
Thus the dilemma of HT1 disease progression is now explained (Fig. 1) but still unsolved: apoptosis resistance leading to accumulation of transformed hepatocytes as well as lack of cell cycle progression and liver regeneration with the consequence of liver failure are both caused exclusively by inappropriate high levels of p21. Simply antagonizing p21, however, is not helpful; rather, it turns out to be carcinogenic in chronic liver diseases. Therefore, p21 alone does not seem to be a promising therapeutic target, especially as the antiproliferative effect of p21 is dose-dependent and fine regulation of p21 expression levels might be problematic. However, the study of Willenbring et al. re-evaluates the important functions of p21 and highlights the high potential of p21 as a diagnostic marker in chronic liver disease.