Characterization of gene expression induced by RET with MEN2A or MEN2B mutation.
Characterization of gene expression induced by RET with MEN2A or MEN2B mutation.
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DOI：
10.1016/s0002-9440(10)64176-4
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发表时间：
2002-07
期刊：
影响因子：
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通讯作者：
Tsuyoshi Watanabe;M. Ichihara;M. Hashimoto;Keiko Shimono;Y. Shimoyama;T. Nagasaka;Y. Murakumo;H. Murakami;H. Sugiura;H. Iwata;N. Ishiguro;Masahide Takahashi
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文献类型：
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作者：
Tsuyoshi Watanabe;M. Ichihara;M. Hashimoto;Keiko Shimono;Y. Shimoyama;T. Nagasaka;Y. Murakumo;H. Murakami;H. Sugiura;H. Iwata;N. Ishiguro;Masahide Takahashi
RET基因的生殖系点突变是导致多发性内分泌瘤（MEN）2A和2B型发展为甲状腺髓样癌和嗜铬细胞瘤的原因。我们使用表达RET-MEN 2A或RET-MEN 2B突变蛋白的NIH 3 T3细胞进行基因表达的差异显示分析。因此，我们确定了10个基因诱导的突变蛋白和8个基因抑制。可诱导基因包括细胞周期蛋白D1、组织蛋白酶B和L以及已知参与细胞生长、肿瘤进展和侵袭的cofilin基因。相反，被抑制的基因包括I型胶原、赖氨酰氧化酶、膜联蛋白I和基质金属蛋白酶组织抑制剂3（TIMP 3）基因，这些基因与肿瘤抑制有关。此外，还鉴定了6个RET-MEN 2A诱导基因和5个RET-MEN 2B诱导基因。在RET-MEN 2A和/或RET-MEN 2 B诱导的21个基因中，包括细胞周期蛋白D1、组织蛋白酶B、cofilin、环指蛋白11（RNF 11）、整合素-α6和斯钙素1（STC 1）的6个基因也在TGW人神经母细胞瘤细胞中响应于胶质细胞系源性神经营养因子刺激而被诱导。由于STC 1基因被发现是高度诱导的RET-MEN 2B和胶质细胞源性神经营养因子刺激，其产物的表达与MEN 2B突变的甲状腺髓样癌通过免疫组化检测，这可能表明STC 1在MEN 2B表型的发展中可能发挥作用。
Germ-line point mutations of the RET gene are responsible for multiple endocrine neoplasia (MEN) type 2A and 2B that develop medullary thyroid carcinoma and pheochromocytoma. We performed a differential display analysis of gene expression using NIH 3T3 cells expressing the RET-MEN2A or RET-MEN2B mutant proteins. As a consequence, we identified 10 genes induced by both mutant proteins and eight genes repressed by them. The inducible genes include cyclin D1, cathepsins B and L, and cofilin genes that are known to be involved in cell growth, tumor progression, and invasion. In contrast, the repressed genes include type I collagen, lysyl oxidase, annexin I, and tissue inhibitor of matrix metalloproteinase 3 (TIMP3) genes that have been implicated in tumor suppression. In addition, six RET-MEN2A- and five RET-MEN2B-inducible genes were identified. Among 21 genes induced by RET-MEN2A and/or RET-MEN2B, six genes including cyclin D1, cathepsin B, cofilin, ring finger protein 11 (RNF11), integrin-α6, and stanniocalcin 1 (STC1) genes were also induced in TGW human neuroblastoma cells in response to glial cell line-derived neurotrophic factor stimulation. Because the STC1 gene was found to be highly induced by both RET-MEN2B and glial cell line-derived neurotrophic factor stimulation, and the expression of its product was detected in medullary thyroid carcinoma with the MEN2B mutation by immunohistochemistry, this may suggest a possible role for STC1 in the development of MEN 2B phenotype.