Mutations and deletions of the CBP gene in human lung cancer.
Mutations and deletions of the CBP gene in human lung cancer.
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发表时间：
2005-01
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通讯作者：
M. Kishimoto;T. Kohno;K. Okudela;A. Otsuka;H. Sasaki;C. Tanabe;T. Sakiyama;C. Hirama;I. Kitabayashi;J. Minna;S. Takenoshita;J. Yokota
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作者：
M. Kishimoto;T. Kohno;K. Okudela;A. Otsuka;H. Sasaki;C. Tanabe;T. Sakiyama;C. Hirama;I. Kitabayashi;J. Minna;S. Takenoshita;J. Yokota
目的 基于微阵列的比较基因组杂交分析使我们检测到肺癌细胞系中环 AMP 反应元件结合蛋白结合蛋白 (CBP) 位点的纯合缺失。功能和遗传学研究已表明 CBP 的致癌作用；因此，通过对人类肺癌中的遗传性CBP改变进行综合分析，研究了CBP基因改变与肺癌发生的关系。实验设计 对 59 个细胞系和 95 个肺癌手术标本进行了突变、纯合和半合缺失以及 CBP 基因表达的分析。结果 在三种 (5.1%) 肺癌细胞系中检测到纯合 CBP 缺失，包括两个基因内缺失。在 6 个 (10.2%) 细胞系和 5 个 (5.3%) 肺癌手术标本中检测到 CBP 突变，包括错义、无义和移码突变。 11例CBP突变病例中有9例保留了野生型CBP等位基因，并且在检查的所有6例杂合CBP突变病例中野生型和突变型等位基因均表达。组蛋白乙酰转移酶结构域中的三个氨基酸取代突变导致 CBP 蛋白体内转录激活活性显着降低。结论 一小部分肺癌携带 CBP 基因突变和/或缺失，表明 CBP 基因改变涉及一部分肺癌的发生和/或进展。
PURPOSE Microarray-based comparative genomic hybridization analysis led us to detect a homozygous deletion at the cyclic AMP response element binding protein-binding protein (CBP) locus in a lung cancer cell line. Oncogenic roles of CBP had been suggested by functional and genetic studies; thus, involvement of CBP gene alterations in lung carcinogenesis was investigated by undertaking comprehensive analysis of genetic CBP alterations in human lung cancer. EXPERIMENTAL DESIGN Fifty-nine cell lines and 95 surgical specimens of lung cancer were analyzed for mutations, homozygous and hemizygous deletions, and expression of the CBP gene. RESULTS Homozygous CBP deletions, including two intragenic deletions, were detected in three (5.1%) lung cancer cell lines. CBP mutations, including missense, nonsense, and frame-shift mutations, were detected in six (10.2 %) cell lines and five (5.3%) surgical specimens of lung cancer. The wild-type CBP allele was retained in 9 of 11 cases with CBP mutations, and both the wild-type and mutant alleles were expressed in all the six cases with heterozygous CBP mutations examined. Three mutations with amino acid substitutions in the histone acetyltransferase domain caused significant reduction in transcription activation activity of CBP protein in vivo. CONCLUSIONS A fraction of lung cancers carried mutations and/or deletions of the CBP gene, suggesting that genetic CBP alterations are involved in the genesis and/or progression of a subset of lung cancers.