Z Gastroenterol 2009; 47 - P3_33
DOI: 10.1055/s-0029-1191890

p53 family-regulated apoptosis genes in hepatocellular carcinoma (HCC)

HM Mundt 1, AF Koch 1, AE Schulze Schleithoff 1, SJ Seitz 1, K Lorenz 1, W Stremmel 1, M Müller 1
  • 1Abt. Innere Medizin IV, Universitätsklinikum Heidelberg

The p53 family genes p53, p63 and p73 produce multiple isoforms that vary in composition of the NH2- and C-termini. The dominant-negative (ΔN) isoforms can oppose the transactivation capabilities of the full length (TA) proteins. The frequent inactivation of p53 and the expression of the ΔN isoforms of p63 and p73 in HCC indicate that abrogation of p53 family-dependent apoptosis could promote hepatocarcinogenesis and confer drug resistance. Therefore, in search for novel strategies to overcome resistance of HCC, this study was designed to characterize the downstream apoptosis genes and signaling pathways regulated by the p53 family in response to cytotoxic drugs.

DNA damaging agents induced accumulation and activation of all three p53 family members (Hep3B cells, Immunoblot) and blocking p53 family function by RNA interference led to chemoresistance of HCC. Microarray analyses revealed that all p53 family members transactivated genes encoding for caspases, death receptors (CD95, TNF-R1, Trail-R1, Trail-R2), and genes of the mitochondrial apoptosis pathway (BCL2L11, BNIP3, DAP3). Following overexpression of the dominant negative (ΔNp63 or ΔNp73) isoforms of the p53 family, these target genes and additional apoptosis-related genes encoding for DAXX, CRADD, PIGPC1, FADD, APAF1, MADD, DAP3, PIG3, DAPK1 were downregulated. This resulted in a significant decrease of apoptosis (confirmed by functional analysis) and conferred chemoresistance.

Upon DNA damage the p53 family engages death receptors, caspases, and mitochondrial apoptosis pathways via transcription-dependent mechanisms. The dominant negative isoforms of the p53 family inhibit the action of the full length isoforms and thus confer drug resistance. Thus, activation or release of TAp63/ TAp73 from mutant p53 or blocking the network of dominant negatives appears to be a promising alternative way of reconstitution of p53, or p53-like activity in HCC.

Apoptose - Chemoresistenz - Genexpression - HCC - p53 - p63 - p73