PROMOTER DELETION AND LOSS OF RETINOBLASTOMA GENE-EXPRESSION IN HUMAN PROSTATE CARCINOMA
PROMOTER DELETION AND LOSS OF RETINOBLASTOMA GENE-EXPRESSION IN HUMAN PROSTATE CARCINOMA
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DOI：
10.1073/pnas.87.19.7762
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发表时间：
1990-10-01
影响因子：
11.1
通讯作者：
LEE, WH
中科院分区：
文献类型：
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作者：
BOOKSTEIN, R;RIO, P;LEE, WH
视网膜母细胞瘤基因（RB）的突变失活存在于所有视网膜母细胞瘤和其他人类肿瘤的一个子集中，包括骨或软组织肉瘤和肺癌或乳腺癌。野生型RB的外源拷贝已被证明可以抑制具有内源性RB突变的几种类型的肿瘤细胞的致瘤性，包括先前描述的人前列腺癌细胞系。为了进一步支持RB失活在前列腺癌发生中的作用，检查了7个原发性或转移性前列腺癌标本中RB突变的证据。通过使用免疫印迹分析和免疫染色的组织切片，RB编码的蛋白很容易检测到肿瘤细胞的5个标本，是可疑的检测在一个标本，显然是不存在的肿瘤细胞的一个标本。在后一种情况下，RB突变被精确地表征为（i）含有转录起始位点的103个核苷酸的缺失和（ii）第二个RB等位基因的缺失。103个碱基对的缺失足以消除异源表达系统中上游DNA序列的启动子活性。这些结果（i）表明RB可以通过其启动子的突变在体内失活，（ii）证实RB突变在某些人前列腺癌中的存在，和（iii）建议使用免疫组化方法来筛选常见成人肿瘤的临床样本中的RB突变。
Mutational inactivation of the retinoblastoma gene (RB) is found in all retinoblastomas and in a subset of other human neoplasms, including sarcomas of bone or soft tissue and carcinomas of lung or breast. Exogenous copies of wild-type RB have been shown to suppress the tumorigenicity of several types of tumor cells with endogenous RB mutations, including a previously described human prostatic carcinoma cell line. To further support a role for RB inactivation in the genesis of prostate cancer, seven primary or metastatic prostate carcinoma specimens were examined for evidence of RB mutation. By the use of immunoblot analysis and immunostaining of histologic sections, RB-encoded protein was readily detected in tumor cells of five specimens, was equivocally detected in one specimen, and was apparently absent from tumor cells of one specimen. RB mutations in the latter case were precisely characterized as (i) a deletion of 103 nucleotides containing transcriptional start sites and (ii) loss of the second RB allele. The 103-base-pair deletion was sufficient to abolish the promoter activity of upstream DNA sequences in a heterologous expression system. These results (i) demonstrate that RB can be inactivated in vivo by mutation of its promoter, (ii) confirm the existence of RB mutations in some human prostate carcinomas, and (iii) suggest the use of immunohistochemical methods to screen for RB mutations in clinical samples of common adult neoplasms.