Insulin-like growth factor I receptor signaling system in JC virus T antigen-induced primitive neuroectodermal tumors-medulloblastomas
Insulin-like growth factor I receptor signaling system in JC virus T antigen-induced primitive neuroectodermal tumors-medulloblastomas
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DOI：
10.1080/13550280290101111
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发表时间：
2002-12-01
影响因子：
3.2
通讯作者：
Reiss, K
中科院分区：
文献类型：
--
作者：
Del Valle, L;Wang, JY;Reiss, K
髓母细胞瘤约占所有儿童颅内肿瘤的25%。这些高度恶性的肿瘤来自小脑，主要影响5至15岁的儿童。虽然髓母细胞瘤的病因尚未阐明，一些报告表明，细胞蛋白胰岛素样生长因子I（IGF-I）和人类多瘤病毒JC（JCV T抗原）的早期蛋白可能有助于这些肿瘤的发展。本研究的结果表明，这两种蛋白质之间的恶性转化过程中的潜在功能合作。成神经管细胞瘤细胞系和成神经管细胞瘤活检的特征在于IGF-I受体（IGF-IR）及其主要信号分子胰岛素受体底物1（IRS-1）的大量存在。重要的是，IRS-1在JCV T抗原存在下易位至细胞核。在T抗原阳性细胞系和诊断为髓母细胞瘤的患者的T抗原阳性活检中检测到核IRS-1。IRS-1结构域负责直接JCV T抗原结合定位在IRS-1分子的N-末端部分，IRS-1的显性阴性突变体对IRS-1 T抗原结合的竞争抑制了JCV T抗原转化细胞在非贴壁培养条件下的生长和存活。
Medulloblastomas represent about 25% of all pediatric intracranial neoplasms. These highly malignant tumors arise from the cerebellum, affecting mainly children between ages 5 and 15. Although the etiology of medulloblastomas has not yet been elucidated, several reports suggest that both the cellular protein insulin-like growth factor I (IGF-I) and the early protein of the human polyomavirus JC (JCV T antigen) may contribute to the development of these tumors. The results of this study show a potential functional cooperation between these two proteins in the process of malignant transformation. Both medulloblastoma cell lines and medulloblastoma biopsies are characterized by the abundant presence of the IGF-I receptor (IGF-IR) and its major signaling molecule, insulin receptor substrate 1 (IRS-1). Importantly, IRS-1 is translocated to the nucleus in the presence of the JCV T antigen. Nuclear IRS-1 was detected in T antigen-positive cell lines and in T antigen-positive biopsies from patients diagnosed with medulloblastoma. The IRS-1 domain responsible for a direct JCV T antigen binding was localized within the N-terminal portion of IRS-1 molecule and the competition for IRS-1 T antigen binding by a dominant-negative mutant of IRS-1 inhibited growth and survival of JCV T antigen-transformed cells in anchorage-independent culture condition.