p53 dephosphorylation and p21(Cip1/Waf1) translocation correlate with caspase-3 activation in TGF-beta1-induced apoptosis of HuH-7 cells.

The p53 tumor suppressor gene product plays an important role in the regulation of apoptosis. Transforming growth factor beta1 (TGF-beta1)-induced apoptosis in hepatic cells is associated with reduced expression of the retinoblastoma protein (pRb) and subsequent E2F-1-activated expression of apoptosis-related genes. In this study, we explored the potential role of p53 in TGF-beta1-induced apoptosis. HuH-7 human hepatoma cells were either synchronized in G1, S and G2/M phases, or treated with 1 nM TGF-beta1. The results indicated that greater than 90% of the TGF-beta1-treated cells were arrested in G1 phase of the cell cycle. This was associated with enhanced p53 dephosphorylation and p21(Cip1/Waf1) expression, which coincided with decreased Cdk2, Cdk4, and cyclin E expression, compared with synchronized G1 cells. In addition, p53 dephosphorylation coincided with caspase-3 activation, and translocation of p21(Cip1/Waf1) and p27(Kip1) into the cytoplasm, all of which were suppressed by caspase inhibition of TGF-beta1-induced apoptosis. Finally, phosphatase inhibition and pRb overexpression partially inhibited p53-mediated apoptosis. In conclusion, the results demonstrated that TGF-beta1-induced p53 dephosphorylation is associated with caspase-3 activation, and cytosolic translocation of p21(Cip1/Waf1) and p27(Kip1), resulting in decreased expression of Cdks and cyclins. Further, p53 appears to mediate TGF-beta1-induced apoptosis downstream of the pRb/E2F-1 pathway.

Fan G ，Ma X ，Wong PY ，Rodrigues CM ，Steer CJ ... -  《APOPTOSIS》

The retinoblastoma gene product inhibits TGF-beta1 induced apoptosis in primary rat hepatocytes and human HuH-7 hepatoma cells.

Fan G ，Ma X ，Kren BT ，Steer CJ ... -  《ONCOGENE》

p53-independent induction of p21(waf1/cip1) contributes to the activation of caspases in GTP-depletion-induced apoptosis of insulin-secreting cells.

Huo JX ，Metz SA ，Li GD 《CELL DEATH AND DIFFERENTIATION》

Clostridium difficile toxin A-induced colonocyte apoptosis involves p53-dependent p21(WAF1/CIP1) induction via p38 mitogen-activated protein kinase.

Kim H ，Kokkotou E ，Na X ，Rhee SH ，Moyer MP ，Pothoulakis C ，Lamont JT ... -  《GASTROENTEROLOGY》

Activation of caspase-8 in transforming growth factor-beta-induced apoptosis of human hepatoma cells.

Shima Y ，Nakao K ，Nakashima T ，Kawakami A ，Nakata K ，Hamasaki K ，Kato Y ，Eguchi K ，Ishii N ... -  《HEPATOLOGY》