Nf2和p53突变在神经嵴起源恶性肿瘤发生中的协同作用。

Synergy of Nf2 and p53 mutations in development of malignant tumours of neural crest origin.

作者信息

Robanus-Maandag Els, Giovannini Marco, van der Valk Martin, Niwa-Kawakita Michiko, Abramowski Vincent, Antonescu Cristina, Thomas Gilles, Berns Anton

机构信息

Division of Molecular Genetics, Centre for Biomedical Genetics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.

出版信息

Oncogene. 2004 Aug 26;23(39):6541-7. doi: 10.1038/sj.onc.1207858.

DOI:10.1038/sj.onc.1207858

PMID:15221010

Abstract

Previously, we have mimicked human neurofibromatosis type 2 (NF2) in conditional Nf2 mutant (P0Cre;Nf2flox2/flox2) mice. Schwannomas, characteristic for NF2, were found at low frequency in older mice. Here, we report that these mice, upon additional hemizygosity for p53, rapidly develop multiple tumours showing features consistent with malignant peripheral nerve sheath tumours. Thus, p53 hemizygosity promotes tumorigenesis of mutant Nf2 peripheral nerve cells. In contrast, young P0Cre;Nf2flox2/+;p53+/- cis mice mainly succumb to Nf2/p53-related osteogenic tumours. Therefore, Cre-mediated early biallelic loss of Nf2 function in neural crest-derived cells hemizygous for p53 results in resistance to osteogenic tumours and increased susceptibility to peripheral nerve sheath tumours.

摘要

此前，我们在条件性Nf2突变（P0Cre;Nf2flox2/flox2）小鼠中模拟了人类2型神经纤维瘤病（NF2）。在老年小鼠中，以低频率发现了NF2特征性的神经鞘瘤。在此，我们报告这些小鼠在p53半合子不足时，会迅速发展出多个具有与恶性外周神经鞘瘤一致特征的肿瘤。因此，p53半合子不足促进了突变型Nf2外周神经细胞的肿瘤发生。相比之下，年轻的P0Cre;Nf2flox2/+;p53+/-顺式小鼠主要死于Nf2/p53相关的成骨性肿瘤。因此，在p53半合子的神经嵴衍生细胞中，Cre介导的Nf2功能早期双等位基因缺失导致对成骨性肿瘤的抗性，并增加对外周神经鞘瘤的易感性。