Ursodeoxycholic acid modulates E2F-1 and p53 expression through a caspase-independent mechanism in transforming growth factor beta1-induced apoptosis of rat hepatocytes.

Susana Sola, Xiaoming Ma, Rui E. Castro, Betsy T. Kren, Clifford J. Steer, Cecilia M.P. Rodrigues

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64 Scopus citations

Abstract

Transforming growth factor beta1 (TGF-beta1)-induced hepatocyte apoptosis is associated with activation of E2F transcription factors and p53 stabilization through Mdm-2, thus potentially modulating a number of target genes. In previous studies, we have shown that ursodeoxycholic acid (UDCA) prevents TGF-beta1-induced hepatocyte apoptosis by inhibiting the mitochondrial pathway of cell death. In this study we examined the role of p53 in the induction of apoptosis by TGF-beta1, and identified additional antiapoptosis targets for UDCA. Our data show a significant transcriptional activation of E2F-1 in primary rat hepatocytes incubated with TGF-beta1, as well as a 5-fold increase in p53 and a 2-fold decrease in its inhibitor, Mdm-2 (p < 0.05). In addition, bax mRNA expression was significantly induced at 36 h (p < 0.01), resulting in increased levels of Bax protein. In contrast, Bcl-2 transcript and protein levels were decreased at all time points (p < 0.01). Notably, UDCA inhibited E2F-1 transcriptional activation, p53 stabilization and Bcl-2 family expression (p < 0.05), in part, through a caspase-independent mechanism. Moreover, in the absence of TGF-beta1, UDCA prevented induction of p53 and Bax by overexpression of E2F-1 and p53, respectively (p < 0.05). In addition, UDCA inhibited TGF-beta1-induced degradation of nuclear factor kappaB (NF-kappaB) and its inhibitor IkappaB (p < 0.05). In conclusion, these results demonstrate that UDCA inhibits E2F-1 transcriptional activation of hepatocyte apoptosis, thus modulating p53 stabilization, NF-kappaB degradation, and expression of Bcl-2 family members.

Original languageEnglish (US)
Pages (from-to)48831-48838
Number of pages8
JournalThe Journal of biological chemistry
Volume278
Issue number49
DOIs
StatePublished - Dec 5 2003

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