Parathyroid hormone-related protein gene expression in human squamous carcinoma cells is repressed by mutant isoforms of p53.
Parathyroid hormone-related protein gene expression in human squamous carcinoma cells is repressed by mutant isoforms of p53.
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发表时间：
1996-09
期刊：
影响因子：
11.2
通讯作者：
J. Foley;J. Wysolmerski;A. Broadus;W. Philbrick
中科院分区：
文献类型：
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作者：
J. Foley;J. Wysolmerski;A. Broadus;W. Philbrick
甲状旁腺增生相关蛋白（PTHrP）是一种正常的分泌产物的各种鳞状上皮细胞，包括表皮角质形成细胞。然而，只有鳞状细胞癌的一个子集，表达的基因水平足以引起体液性高钙血症。在本研究中，比较PTHrP表达水平与p53功能状态在一系列的鳞状细胞癌细胞系之间的关联揭示了特定的突变亚型的p53和非常低的PTHrP mRNA水平的表达。密码子248和273突变的p53亚型的评估表明，它们能够抑制PTHrP基因在高表达，p53阴性鳞状细胞系中的表达约50%。相反，内源性突变体p53与E1B蛋白的失活导致PTHrP在低表达细胞系中的表达增加。随后的分析启动子特异性PTHrP转录在p53阴性鳞状细胞系转染突变型p53亚型表明，下调主要发生在两个TATA为基础的启动子。在瞬时转染试验中对鼠PTHrP报告基因构建体的直接测试证实了248和273突变体抑制这种基于TATA的启动子的能力，尽管只有野生型p53的一半有效。
Parathyroid hormone-related protein (PTHrP) is a normal secretory product of a variety of squamous epithelia, including epidermal keratinocytes. Only a subset of squamous carcinomas, however, express the gene at levels sufficient to cause humoral hypercalcemia. In the present study, comparison of PTHrP expression levels with p53 functional status in a series of squamous carcinoma lines has revealed an association between expression of specific mutant isoforms of p53 and very low levels of PTHrP mRNA. Evaluation of p53 isoforms with mutations in codons 248 and 273 showed them to be capable of repressing PTHrP gene expression in a high-expressing, p53-negative squamous line by approximately 50%. Conversely, inactivation of an endogenous mutant p53 with E1B proteins resulted in an increase in PTHrP expression in a low-expressing cell line. Subsequent analysis of promoter-specific PTHrP transcripts in a p53-negative squamous line transfected with mutant p53 isoforms suggested that down-regulation occurred primarily at the two TATA-based promoters. Direct testing of a murine PTHrP reporter construct in transient transfection assays confirmed the capacity of the 248 and 273 mutants to repress this TATA-based promoter, although only about half as effectively as wild-type p53.