The neural progenitor-restricted isoform of the MARK4 gene in 19q13.2 is upregulated in human gliomas and overexpressed in a subset of glioblastoma cell lines
The neural progenitor-restricted isoform of the MARK4 gene in 19q13.2 is upregulated in human gliomas and overexpressed in a subset of glioblastoma cell lines
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DOI：
10.1038/sj.onc.1206336
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发表时间：
2003-05-01
期刊：
影响因子：
8
通讯作者：
Larizza, L
中科院分区：
文献类型：
--
作者：
Beghini, A;Magnani, I;Larizza, L
19q13 的改变在神经胶质肿瘤中经常观察到，表明该区域至少含有一种与神经胶质瘤发生有关的基因。根据我们之前对胶质瘤结构 19q 染色体重排的研究，我们对断点进行了详细的 FISH 分析，并在三种原代胶质母细胞瘤细胞系中鉴定了 MAP/微管亲和力调节激酶 4 (MARK4) 基因的 19q13.2 染色体内扩增。最近的数据表明该基因参与 Wnt 信号通路。我们观察到，可变剪接的 MARK4L 亚型的表达在新鲜和培养的胶质瘤中均上调，并且在所有上述三种胶质母细胞瘤细胞系中过表达。有趣的是，我们还发现MARK4L表达仅限于未分化的神经祖细胞或增殖的神经胶质前体细胞，而其表达在神经胶质分化过程中下调。在胶质母细胞瘤细胞中使用针对 MARK4 的反义寡核苷酸扰乱表达，始终诱导肿瘤细胞增殖减少。总而言之，这些数据表明，通常在神经祖细胞中表达的 MARK4 在神经胶质瘤中重新表达，并可能成为 19q 重排时染色体内扩增的关键靶标。
Alterations of 19q13 are frequently observed in glial neoplasms, suggesting that this region harbors at least one gene involved in gliomagenesis. Following our previous studies on structural 19q chromosome rearrangements in gliomas, we have undertaken a detailed FISH analysis of the breakpoints and identified a 19q13.2 intrachromosomal amplification of the MAP/microtubule affinity-regulating kinase 4 (MARK4) gene in three primary glioblastoma cell lines. Recent data suggest that this gene is involved in the Wnt-signating pathway. We observed that the expression of the alternatively spliced MARK4L isoform is upregulated in both fresh and cultured gliomas and overexpressed in all of the above three glioblastoma cell lines. Interestingly, we also found that MARK4L expression is restricted to undifferentiated neural progenitor cells or proliferating glial precursor cells, whereas its expression is downregulated during glial differentiation. Perturbation of expression using antisense oligonucleotides against MARK4 in glioblastoma cell tines, consistently induced a decreased proliferation of tumor cells. Taken together, these data show that MARK4, which is normally expressed in neural progenitors, is re-expressed in gliomas and may become a key target of intrachromosomal amplification upon 19q rearrangements.