Henriksen Jørn, Aagesen Trude H, Maelandsmo Gunhild M, Lothe Ragnhild A, Myklebost Ola, Forus Anne
Department of Tumour Biology, Institute of Cancer Research, The Norwegian Radium Hospital, 0310 Oslo, Norway.
Oncogene. 2003 Aug 14;22(34):5358-61. doi: 10.1038/sj.onc.1206671.
In sarcomas, the TP53 tumour suppressor pathway may be altered either by TP53 mutations or by amplification of MDM2, encoding a protein that inhibits TP53 and targets it for 26S-proteasome degradation. However, in the majority of the analysed clinical samples, neither of these types of aberrations are found, suggesting that additional mechanisms are involved. The present study shows that COPS3, located in 17p11 and encoding a component of the proteasome pathway, is more frequently amplified in osteosarcomas (OS) than is MDM2. We present detailed analysis of TP53 mutations and MDM2 and COPS3 expression levels in a set of 23 OS. Our results show that none of the tumours with COPS3 amplification had MDM2 amplification nor TP53 mutations, consistent with the hypothesis that one of the three aberrations is sufficient. The results suggest that inactivation of otherwise intact TP53 by aberrations in the proteasome pathway may contribute to the characteristic aneuploidy observed in OS.
在肉瘤中，TP53肿瘤抑制通路可能通过TP53突变或MDM2扩增而发生改变，MDM2编码一种抑制TP53并将其靶向26S蛋白酶体降解的蛋白质。然而，在大多数分析的临床样本中，未发现这两种类型的畸变，这表明还涉及其他机制。本研究表明，位于17p11且编码蛋白酶体通路一个组分的COPS3，在骨肉瘤（OS）中比MDM2更频繁地发生扩增。我们对一组23例骨肉瘤中的TP53突变以及MDM2和COPS3表达水平进行了详细分析。我们的结果显示，COPS3扩增的肿瘤均无MDM2扩增和TP53突变，这与三种畸变之一就足够的假设一致。结果表明，蛋白酶体通路的畸变使原本完整的TP53失活，可能导致骨肉瘤中观察到的特征性非整倍体。
