Tissue-Specific Ablation of Prkar1a Causes Schwannomas by Suppressing Neurofibromatosis Protein Production
Tissue-Specific Ablation of Prkar1a Causes Schwannomas by Suppressing Neurofibromatosis Protein Production
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DOI：
10.1593/neo.08652
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发表时间：
2008-11-01
期刊：
影响因子：
4.8
通讯作者：
Kirschner, Lawrence S.
中科院分区：
文献类型：
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作者：
Jones, Georgette N.;Tep, Chhavy;Kirschner, Lawrence S.
在神经纤维瘤病（NF）的背景下，导致雪旺细胞肿瘤启动的信号事件已被广泛表征。在患有内分泌肿瘤综合征Carney综合征的患者中也观察到类似的肿瘤，该综合征由PRKAR1A中的失活突变引起。PRKAR1A的缺失导致蛋白激酶A活性增强，尽管导致肿瘤发生的途径还没有得到很好的表征。在神经嵴前体细胞（TEC3KO小鼠）中Prkar1a的组织特异性消融导致神经鞘瘤，10个月时接近80%的存活率。这些异质性肿瘤的临床特征为基因工程小鼠神经鞘瘤，II级和III级。在分子水平上，对肿瘤的分析显示两种NF蛋白几乎完全丢失，尽管转录水平增加，这意味着转录后调节。尽管Erk和Akt信号在NF相关肿瘤中通常增强，但我们在TEC3KO肿瘤中没有观察到这些途径的激活。此外，已知小G蛋白Ras、Rac1和RhoA都参与NF信号传导。在TEC3KO肿瘤中，所有三种分子均显示总蛋白适度增加，但只有Rac1显示出显著活化。这些数据表明，失调的蛋白激酶A激活导致肿瘤发生的途径重叠，但不同的NF肿瘤发生中所描述的。
Signaling events leading to Schwann cell tumor initiation have been extensively characterized in the context of neurofibromatosis (NF). Similar tumors are also observed in patients with the endocrine neoplasia syndrome Carney complex, which results from inactivating mutations in PRKAR1A. Loss of PRKAR1A causes enhanced protein kinase A activity, although the pathways leading to tumorigenesis are not well characterized. Tissue-specific ablation of Prkar1a in neural crest precursor cells (TEC3KO mice) causes schwannomas with nearly 80% penetrance by 10 months. These heterogeneous neoplasms were clinically characterized as genetically engineered mouse schwannomas, grades II and III. At the molecular level, analysis of the tumors revealed almost complete loss of both NF proteins, despite the fact that transcript levels were increased, implying posttranscriptional regulation. Although Erk and Akt signaling are typically enhanced in NF-associated tumors, we observed no activation of either of these pathways in TEC3KO tumors. Furthermore, the small G proteins Ras, Rac1, and RhoA are all known to be involved with NF signaling. In TEC3KO tumors, all three molecules showed modest increases in total protein, but only Rac1 showed significant activation. These data suggest that dysregulated protein kinase A activation causes tumorigenesis through pathways that overlap but are distinct from those described in NF tumorigenesis.