Involvement of LIM domain proteins and Lbd2 in the lung tissue development and carcinogensis.

LIM 结构域蛋白和 Lbd2 参与肺组织发育和致癌作用。

• 批准号: 11670158
• 负责人: OSADA Hirotaka
• 金额: $ 2.11万
• 依托单位: Aichi Cancer Center
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11670158/
• 关键词: Lung Cancer; Oncogene; 肺癌; LIMドメイン

We previously isolated the human LIMK2 gene and identified two alternative transcripts, LIMK2a and LIMK2b, which were differentially regulated in a tissue-specific manner. To investigate this mechanism and the transcription factors involved, we isolated the LIMK2a and 2b promoters. A luciferase reporter assay of the transcriptional activity revealed positive as well as negative regulatory regions within both promoters. The co-transfection assay suggested that the transcription factor, MZF-1, might regulate the expression of the LIMK2 isoforms in a different manner. The nuclear recptor, RORα1, might also be involved in the transcriptional regulation of the LIMK2b isoform. These findings should lead to a better understanding of the possibly diverse functions of the LIMK family.We also isolated and studied the Ldb2 gene. The Ldb2 had the strong binding specificity to nuclar LIM proteins, which were thought to be involeved in the transcriptional regulation. The expression pattern of Ldb2 and its homologue Ldb1 were studied. The Ldb2 is expressed preferentially in normal lung, while the Ldb1 expression is increased in lung cancer tissues, suggesting the differential involvement of these genes in lung carcinogensis. We also examined the status of the Ldb2 gene in lung cancer cell lines. However, we could not find any genetic alteration.

我们以前分离的人LIMK 2基因，并确定了两个替代的转录本，LIMK 2a和LIMK 2b，这是差异调节的组织特异性的方式。为了研究这种机制和涉及的转录因子，我们分离了LIMK 2a和2b启动子。一个荧光素酶报告基因的转录活性检测显示，积极的，以及负调控区域内的两个启动子。共转染实验表明，转录因子MZF-1可能以不同的方式调节LIMK 2亚型的表达。核受体RORα1也可能参与LIMK 2b亚型的转录调控。这些发现将有助于我们更好地理解LIMK家族可能的不同功能。我们还分离并研究了Ldb 2基因。Ldb 2与核LIM蛋白具有较强的结合特异性，这些蛋白被认为参与转录调控。研究了Ldb 2及其同源物Ldb 1的表达模式。Ldb 2在正常肺组织中优先表达，而Ldb 1在肺癌组织中表达增加，提示这些基因在肺癌发生中的差异参与。我们还研究了Ldb 2基因在肺癌细胞系中的状态。但是，我们没有发现任何基因改变。

项目成果

Nomoto, S., Haruki, N., Takahashi, T., Masuda, A., Koshikawa, T., Takahashi, T., Fujii, Y., Osada, H., and Takahashi, T.: "Search for in vivo somatic mutations in the mitotic checkpoint gene hMAD1, in human lung cancers"Oncogene. 18. 7180-7183 (1999)

Nomoto, S.、Haruki, N.、Takahashi, T.、Masuda, A.、Koshikawa, T.、Takahashi, T.、Fujii, Y.、Osada, H. 和 Takahashi, T.：“搜索

Haruki, N., Saito, H., Harano, T., Nomoto, S., Takahashi, T., Osada, H., Fujii, F., Takahashi, T.: "Molecular Analysis of the Mitotic Checkpoint Genes BUB1, BUBR1 and BUB3 in Human Lung Cancers."Cancer Letters. 162. 201-205 (2001)

Haruki, N.、Saito, H.、Harano, T.、Nomoto, S.、Takahashi, T.、Osada, H.、Fujii, F.、Takahashi, T.：“有丝分裂检查点基因 BUB1 的分子分析，

Yanagisawa,K., et al.: "Heterogeneities in the biological and biochemical functions of Smad2 and Smad4 mutants naturally occurring in human lung cancers."Oncogene. 19・19. 2305-2311 (2000)

Yanagisawa, K., et al.：“人类肺癌中天然存在的 Smad2 和 Smad4 突变体的生物学和生化功能的异质性。”19・19 (2000)。

Haruki,N., et al.: "Histological type-selective, tumor-predominant expression of a novel CHK1 isoform and infrequent in vivo somatic CHK2 mutation in small cell lung cancer."Cancer Research. 60・17. 4689-4692 (2000)

Haruki, N., 等人：“小细胞肺癌中一种新型 CHK1 异构体的组织学类型选择性、肿瘤主导表达和罕见的体内体细胞 CHK2 突变。”癌症研究 60・17（2000 年）。 ）

Haruki, N., Yatabe, Y., Travis, W.D., Nomoto, S., Osada, H., Nakamura, S., Nakao, A., Fujii, Y., and Takahashi, T.: "Homo- and heterogeneity within high-grade neuroendocrine tumors of the lung."Jpn. J.Cancer Res. 91. 317-323 (2000)

Haruki, N.、Yatabe, Y.、Travis, W.D.、Nomoto, S.、Osada, H.、Nakamura, S.、Nakao, A.、Fujii, Y. 和 Takahashi, T.：“同质性和异质性