The activating mutation R201C in GNAS promotes intestinal tumourigenesis in Apc(Min/+) mice through activation of Wnt and ERK1/2 MAPK pathways.
The activating mutation R201C in GNAS promotes intestinal tumourigenesis in Apc(Min/+) mice through activation of Wnt and ERK1/2 MAPK pathways.
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DOI：
10.1038/onc.2010.202
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发表时间：
2010-08-12
期刊：
影响因子：
8
通讯作者：
Adams, D. J.
中科院分区：
文献类型：
--
作者：
Wilson, C. H.;McIntyre, R. E.;Arends, M. J.;Adams, D. J.
GNAS（编码刺激性 G 蛋白 Gsα 亚基的基因）的体细胞获得性激活突变已在肾脏、甲状腺、垂体、间质细胞、肾上腺皮质以及最近的结直肠肿瘤中被发现，表明 R201C 等突变可能在这些组织中致癌。为了研究 GNAS 在肠道肿瘤发生中的作用，我们将 GNAS R201C 置于 A33 抗原启动子 (Gpa33) 的控制下，该启动子几乎只在肠道中表达。 GNAS R201C 突变已被证明会导致 Gsα 和腺苷酸环化酶的组成型激活，并导致 cAMP 的自主合成。 Gpa33tm1(GnasR201C)Wtsi/+小鼠表现出肠上皮中cAMP水平显着升高和cAMP特异性磷酸二酯酶的补偿性上调。单独的 GNAS R201C 不足以在 12 个月时诱导肿瘤发生，但当 Gpa33tm1(GnasR201C)Wtsi/+ 小鼠在 ApcMin/+ 背景下饲养时，腺瘤形成显着增加。 GNAS R201C 表达与 Wnt 和细胞外信号调节激酶 1/2 丝裂原激活蛋白激酶 (ERK1/2 MAPK) 途径靶基因表达升高、ERK1/2 MAPK 磷酸化增加以及增殖标记物 Ki67 免疫染色增加相关。此外，GNAS R201C 对 Wnt 通路的影响会导致 Apc 失活。我们的数据强烈表明 GNAS 的激活突变与 APC 的失活协同作用，并可能导致结直肠肿瘤的发生。
Somatically acquired, activating mutations of GNAS, the gene encoding the stimulatory G-protein Gsα subunit, have been identified in kidney, thyroid, pituitary, leydig cell, adrenocortical and more recently, in colorectal tumours, suggesting that mutations such as R201C may be oncogenic in these tissues. To study the role of GNAS in intestinal tumourigenesis, we placed GNAS R201C under the control of the A33-antigen promoter (Gpa33), which is almost exclusively expressed in the intestines. The GNAS R201C mutation has been shown to result in the constitutive activation of Gsα and adenylate cyclase and to lead to the autonomous synthesis of cAMP. Gpa33tm1(GnasR201C)Wtsi/+ mice showed significantly elevated cAMP levels and a compensatory upregulation of cAMP-specific phosphodiesterases in the intestinal epithelium. GNAS R201C alone was not sufficient to induce tumourigenesis by 12 months but there was a significant increase in adenoma formation when Gpa33tm1(GnasR201C)Wtsi/+ mice were bred onto an ApcMin/+ background. GNAS R201C expression was associated with elevated expression of Wnt and extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase (ERK1/2 MAPK) pathway target genes, increased phosphorylation of ERK1/2 MAPK, and increased immunostaining for the proliferation marker Ki67. Furthermore, the effects of GNAS R201C on the Wnt pathway were additive to inactivation of Apc. Our data strongly suggest that activating mutations of GNAS cooperate with inactivation of APC and are likely to contribute to colorectal tumourigenesis.
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影响因子：
3.9
作者：
Kotoula, Vassiliki;Sozopoulos, Elias;Mitsiades, Nicholas
通讯作者：
Mitsiades, Nicholas
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LANDIS, CA;MASTERS, SB;VALLAR, L
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VALLAR, L
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作者：
Haigis, Kevin M.;Kendall, Krystle R.;Jacks, Tyler
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Jacks, Tyler
影响因子：
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作者：
Kirschner, LS;Carney, JA;Stratakis, CA
通讯作者：
Stratakis, CA
影响因子：
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作者：
DIETRICH, WF;LANDER, ES;DOVE, W
通讯作者：
DOVE, W