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 deficiency in mice does not lead to a cancer-prone phenotype, and p73 gene is not mutated in human cancers, including hepatocellular carcinoma. Here we report that normal liver cells express only ΔN-p73 transcript forms giving rise to the synthesis of N-terminally 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 ΔN-p73. We also show that together with the acquired expression of TA-p73, the ‘retinoblastoma pathway’ is inactivated, and E2F1-target genes including cyclin E and p14ARF 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 ΔN-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.
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Abbreviations
- HCC:
-
hepatocellular carcinoma
- RB1:
-
retinoblastoma gene
- pRb:
-
retinoblastoma protein
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Acknowledgements
This work was supported by a grant from TUBITAK (Turkey). We would like to thank B Carr (University of Pittsburgh, PA, USA) for providing Hep40 and Hep3B-TR cell lines, D Bellet (Institut Gustave Roussy, France) for JAR13 antibody, R Cetin-Atalay for critical reading of the manuscript, T Cagatay for DNA sequencing work, C Akcali's group for animal surgery, and G Tuncman for help in RNA studies.
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Sayan, A., Sayan, B., Findikli, N. et al. Acquired expression of transcriptionally active p73 in hepatocellular carcinoma cells. Oncogene 20, 5111–5117 (2001). https://doi.org/10.1038/sj.onc.1204669
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DOI: https://doi.org/10.1038/sj.onc.1204669
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