Sayan A E, Sayan B S, Findikli N, Ozturk M
Department of Molecular Biology and Genetics, Bilkent University, 06533, Ankara, Turkey.
Oncogene. 2001 Aug 23;20(37):5111-7. doi: 10.1038/sj.onc.1204669.
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 DeltaN-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 DeltaN-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 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 DeltaN-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.
p53和p73蛋白激活相似的靶基因，并诱导细胞凋亡和细胞周期停滞。然而，p53被认为是一种肿瘤抑制基因，而p73不是。与p53不同，小鼠缺乏p73不会导致易患癌症的表型，并且在包括肝细胞癌在内的人类癌症中p73基因不会发生突变。在此我们报告，正常肝细胞仅表达DeltaN-p73转录本形式，从而导致合成N端截短、转录无活性且具有显性负性作用的p73蛋白。相反，除了DeltaN-p73之外，大多数肝癌细胞还表达编码全长且具有转录活性的p73蛋白的TA-p73转录本形式。我们还表明，随着TA-p73的获得性表达，“视网膜母细胞瘤通路”失活，并且包括细胞周期蛋白E和p14(ARF)在内的E2F1靶基因在肝癌中被激活。然而，“视网膜母细胞瘤通路”失活与TA-p73表达之间并没有完全的相关性。大多数表达TA-p73的肝癌细胞也通过缺乏表达或错义突变而失去了p53功能。仅编码DeltaN-p73蛋白的p73基因在肝组织中可能起到肿瘤促进因子而非肿瘤抑制因子的作用。这可能是p73在肝细胞癌中不是突变靶点的原因之一。
