Inactivation of human SRBC, located within the 11p15.5-p15.4 tumor suppressor region, in breast and lung cancers.
Inactivation of human SRBC, located within the 11p15.5-p15.4 tumor suppressor region, in breast and lung cancers.
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发表时间：
2001-11
期刊：
影响因子：
11.2
通讯作者：
X. L. Xu;L. Wu;F. Du;A. Davis;M. Peyton;Y. Tomizawa;A. Maitra;G. Tomlinson;A. Gazdar
中科院分区：
文献类型：
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作者：
X. L. Xu;L. Wu;F. Du;A. Davis;M. Peyton;Y. Tomizawa;A. Maitra;G. Tomlinson;A. Gazdar
以BRCA 1的氨基酸1-304为探针，在酵母双杂交筛选中分离出编码人SRBC [血清剥夺反应因子（sdr）相关基因产物，与c-激酶结合]的cDNA克隆。人SRBC基因定位于染色体11 p15.5-p15.4区域，靠近标记D11 S1323，在该区域，在散发性乳腺癌、肺癌、卵巢癌和其他类型的成人肿瘤以及儿童肿瘤中观察到频繁的杂合性丢失（洛）。在少数卵巢癌和肺癌细胞系中检测到hSRBC编码区突变，包括移码和截短突变。更重要的是，hSRBC蛋白的表达在大部分乳腺癌、肺癌和卵巢癌细胞系中下调[30（70%）/43]，而在正常乳腺癌和肺上皮细胞中检测到hSRBC蛋白的强表达。癌细胞中hSRBC表达的下调与其启动子区CpG二核苷酸的高甲基化有关，并且5例原发性乳腺肿瘤中的3例（60%）和14例原发性肺肿瘤中的11例（79%）也被发现是高甲基化的。用5 '氮杂胞苷和曲古抑菌素A处理乳腺癌MCF 7细胞导致hSRBC的表达，证实DNA甲基化是失活模式。我们的研究结果表明，hSRBC的表观遗传或突变失活可能有助于几种类型的人类癌症的发病机制，标志着hSRBC作为一个候选的肿瘤抑制基因。
A cDNA clone encoding human SRBC [serum deprivation response factor (sdr)-related gene product that binds to c-kinase] was isolated in a yeast two-hybrid screening, with amino acids 1-304 of BRCA1 as the probe. The human SRBC gene (hSRBC) was mapped to chromosome region 11p15.5-p15.4, close to marker D11S1323, at which frequent loss of heterozygosity (LOH) has been observed in sporadic breast, lung, ovarian, and other types of adult cancers as well as childhood tumors. hSRBC-coding region mutations including frame shift and truncation mutations were detected in a few ovarian and lung cancer cell lines. More significantly, the expression of hSRBC protein was down-regulated in a large fraction [30 (70%) of 43] of breast, lung, and ovarian cancer cell lines, whereas strong expression of hSRBC protein was detected in normal mammary and lung epithelial cells. The down-regulation of hSRBC expression in cancer cells was associated with hypermethylation of CpG dinucleotides in its promoter region, and 3 (60%) of 5 primary breast tumors and 11 (79%) of 14 primary lung tumors were also found to be hypermethylated. Treatment of breast cancer MCF7 cells with 5'azacytidine and Trichostatin A resulted in expression of hSRBC, confirming DNA methylation as the mode of inactivation. Our results suggest that epigenetic or mutational inactivation of hSRBC may contribute to the pathogenesis of several types of human cancers, marking hSRBC as a candidate tumor suppressor gene.