Acquired expression of transcriptionally active p73 in hepatocellular carcinoma cells

Abstract

p53 and p73 proteins activate similar target genes and induce apoptosis and cell cycle arrest. However, p53, but not p73 is considered a tumour-suppressor gene. Unlike p53, p73 de®ciency in mice does not lead to a cancerprone phenotype, and p73 gene is not mutated in human cancers, including hepatocellular carcinoma. Here we report that normal liver cells express only DN-p73 transcript forms giving rise to the synthesis of Nterminally truncated, transcriptionally inactive and dominant negative p73 proteins. In contrast, most hepatocellular carcinoma cells express TA-p73 transcript forms encoding full-length and transcriptionally active p73 proteins, in addition to DN-p73. We also show that together with the acquired expression of TA-p73, thè retinoblastoma pathway' is inactivated, and E2F1-target genes including cyclin E and p14 ARF are activated in hepatocellular carcinoma. However, there was no full correlation between`retinoblastoma pathway' inactivation and TA-p73 expression. Most TA-p73-expressing hepatocellular carcinoma cells have also lost p53 function either by lack of expression or missense mutations. The p73 gene, encoding only DN-p73 protein, may function as a tumour promoter rather than a tumour suppressor in liver tissue. This may be one reason why p73 is not a mutation target in hepatocellular carcinoma. Oncogene (2001) 20, 5111 ± 5117.

p73 and caspase-cleaved p73 fragments localize to mitochondria and augment TRAIL-induced apoptosis

“…The TP53 gene is mutated and mutant p53 protein is accumulated in at least 50% of cancers (Sigal and Rotter, 2000). On the other hand, the TP73 gene is very rarely mutated and overexpression of TAp73 is often observed in tumors (Zaika et al, 1999;Stiewe and Putzer, 2000;Sayan et al, 2001;Muller et al, 2005). The new transcriptionindependent function of p73 and p53 (Sayan et al, 2006) suggests new approaches to chemotherapy, which do not require transcriptionally active p53 family members.…”

Dinucleotide polymorphism of p73 gene is associated with a reduced risk of lung cancer in a Chinese population

“…14,22 However, detailed analysis of the p73 protein in tumor tissues has revealed that there are 2 p73 isoforms, DeltaTA-p73 and DeltaN- p73, which play opposing roles in carcinogenesis. [23][24][25][26][27] Very recently, Concin et al 28 reported that only the spliced DeltaTA-p73 transcripts from the TA promoter show significantly increased expression levels in the tumor, whereas the DeltaN-p73 transcript generated from the second promoter is not significantly up-regulated. Supporting evidence was also obtained from recently studies in vulval cancer and in hepatocellular carcinoma.…”

p53 mutation as a source of aberrant β-catenin accumulation in cancer cells

“…The origins and culture conditions of HCC cell lines used here have been reported recently (Sayan et al, 2001a). HepG2 and SK-Hep1 cell line clones ectopically expressing mutant forms (p53-V143A, p53-R248W, p53-R249S) of p53 were generated by stable transfection with appropriate plasmids (Frebourg et al, 1992), as described previously (Ponchel et al, 1994).…”

“…Detergent-soluble cell lysates were prepared and used for the analysis of total b-catenin and p53 protein levels by western blot assay, as described previously (Sayan et al, 2001a). Cytosolic and non-cytosolic forms of b-catenin were analysed on protein lysates prepared from corresponding cellular fractions.…”

“…Total RNA was extracted and used for cDNA synthesis and semi-quantitative RT -PCR analysis, as described previously (Sayan et al, 2001a), using a b-catenin primer pair derived from exons 2 and 4, respectively (Koch et al, 1999), allowing to detect differentially the expression of wild-type and truncated b-catenin transcripts in HepG2 cells which displays a heterozygous interstitial deletion of b-catenin gene between exons 2 and 4 (de La Coste et al, 1998).…”