A Novel Mechanism of the p53 Isoform Δ40p53α in Regulating Collagen III Expression in TGFβ1-Induced LX-2 Human Hepatic Stellate Cells

Abstract

Injured liver cells undergoing chronic wound healing produce excessive amounts of extracellular matrix (ECM) components, such as collagen and fibronectin, leading to fibrosis. This process is largely mediated by transforming growth factor-β (TGFβ) signaling, which intersects with the tumor suppressor p53 pathway. However, the roles of specific p53 isoforms in this interaction remain unclear. In this study, we report the involvement of the Δ40p53α isoform, an N-terminal truncated variant of p53, in regulating ECM gene expression in TGFβ1-activated LX-2 human hepatic stellate cells. RT-PCR analysis of cirrhotic liver tissues revealed clinically relevant increases in Δ40p53 expression. Knockdown of Δ40p53 using antisense oligonucleotides in LX-2 cells attenuated TGFβ1-induced activation and significantly reduced collagen production and deposition, particularly fibrillar collagen III. Conversely, overexpression of Δ40p53α upregulated collagen III expression in concert with full-length p53 (FLp53). Co-immunoprecipitation analysis demonstrated that Δ40p53α forms a complex with FLp53, which associates with phosphorylated Smad3 following TGFβ1 stimulation. These findings suggest that Δ40p53 enhances collagen III expression by interacting with FLp53 and Smads, highlighting its role in profibrogenic ECM expression.