Epidermal growth factor receptor and Ink4a/Arf:: Convergent mechanisms governing terminal differentiation and transformation along the neural stem cell to astrocyte axis
Epidermal growth factor receptor and Ink4a/Arf:: Convergent mechanisms governing terminal differentiation and transformation along the neural stem cell to astrocyte axis
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DOI：
10.1016/s1535-6108(02)00046-6
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发表时间：
2002-04-01
期刊：
影响因子：
50.3
通讯作者：
DePinho, RA
中科院分区：
文献类型：
--
作者：
Bachoo, RM;Maher, EA;DePinho, RA
Ink 4a/Arf失活和表皮生长因子受体（EGFR）激活是高级别胶质瘤的标志性病变。这些突变如何介导这些肿瘤的生物学特征尚不清楚。在这里，我们证明了p16（INK 4a）和p19（ARF）的联合丢失，而不是p53，p16（INK 4a）或p19（ARF），使星形胶质细胞去分化对EGFR激活的反应。此外，具有组成型活性EGFR的Ink 4a/Arf（-/-）神经干细胞（NSC）或星形胶质细胞的转导诱导常见的高级别胶质瘤表型。这些研究结果确定神经干细胞和星形胶质细胞作为同样允许的胶质瘤形成的隔间，并提供证据表明，p16（INK 4a）和p19（ARF）协同维持终末星形胶质细胞分化。这些数据支持这样的观点，即特定遗传通路的失调，而不是细胞的起源，决定了高级别胶质瘤的出现和表型。
Ink4a/Arf inactivation and epidermal growth factor receptor (EGFR) activation are signature lesions in high-grade gliomas. How these mutations mediate the biological features of these tumors is poorly understood. Here, we demonstrate that combined loss of p16(INK4a) and p19(ARF), but not of p53, p16(INK4a), or p19(ARF), enables astrocyte dedifferentiation in response to EGFR activation. Moreover, transduction of Ink4a/Arf(-/-) neural stem cells (NSCs) or astrocytes with constitutively active EGFR induces a common high-grade glioma phenotype. These findings identify NSCs and astrocytes as equally permissive compartments for gliomagenesis and provide evidence that p16(INK4a) and p19(ARF) synergize to maintain terminal astrocyte differentiation. These data support the view that dysregulation of specific genetic pathways, rather than cell-of-origin, dictates the emergence and phenotype of high-grade gliomas.