Cell type-specific tumor suppression by Ink4a and Arf in Kras-induced mouse gliomagenesis.
Cell type-specific tumor suppression by Ink4a and Arf in Kras-induced mouse gliomagenesis.
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DOI：
10.1158/0008-5472.can-04-3588
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发表时间：
2005-03
期刊：
影响因子：
11.2
通讯作者：
Lene Uhrbom;M. Kastemar;Fredrik K Johansson;B. Westermark;E. Holland
中科院分区：
文献类型：
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作者：
Lene Uhrbom;M. Kastemar;Fredrik K Johansson;B. Westermark;E. Holland
INK 4a-ARF基因座的纯合性缺失是在人类胶质母细胞瘤中发现的最常见的突变之一。我们先前已经表明，在小鼠胶质瘤发生过程中，Ink 4a-Arf的联合缺失可以增加胶质祖细胞和星形胶质细胞中的肿瘤发生率。在这里，我们研究了Akt + Kras诱导的胶质瘤形成中胶质祖细胞和星形胶质细胞中每种肿瘤抑制基因丢失的单独贡献。我们发现，Arf是主要的肿瘤抑制基因在这两种细胞类型。Arf缺失产生的胶质母细胞瘤来自表达nestin的胶质祖细胞和表达胶质酸性蛋白的星形胶质细胞，星形胶质细胞中的发病率显著较高。另一方面，Ink 4a缺失只能显著促进胶质祖细胞的胶质瘤形成，并且诱导的肿瘤的恶性度低于Arf缺陷小鼠中所见的恶性度。因此，Ink 4a和Arf在体内的胶质细胞隔室中具有独立和差异的肿瘤抑制功能。
Homozygous deletion of the INK4a-ARF locus is one of the most frequent mutations found in human glioblastoma. We have previously shown that combined Ink4a-Arf loss can increase tumor incidence in both glial progenitor cells and astrocytes during mouse gliomagenesis. Here we have investigated the separate contribution of loss of each of the tumor suppressor genes in glial progenitor cells and astrocytes in Akt + Kras-induced gliomagenesis. We show that Arf is the major tumor suppressor gene in both cell types. Arf loss generated glioblastomas from both nestin-expressing glial progenitor cells and glial fibrillary acidic protein-expressing astrocytes, with a significantly higher incidence in astrocytes. Ink4a loss, on the other hand, could only significantly contribute to gliomagenesis from glial progenitor cells and the induced tumors were of lower malignancy than those seen in Arf-deficient mice. Thus, Ink4a and Arf have independent and differential tumor suppressor functions in vivo in the glial cell compartment.