Alternative splicing of parathyroid hormone-related protein mRNA: expression and stability
Alternative splicing of parathyroid hormone-related protein mRNA: expression and stability
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DOI：
10.1677/jme.0.0330227
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发表时间：
2004-08-01
影响因子：
3.5
通讯作者：
Rosol, TJ
中科院分区：
文献类型：
--
作者：
Sellers, RS;Luchin, AI;Rosol, TJ
甲状旁腺相关蛋白（PTHrP）是一种多功能蛋白质，通常在癌症中失调。人PTHrP基因被选择性剪接成三种同种型，每种同种型具有独特的3 '-非翻译区（3'-UTR），编码139、173和141个氨基酸的蛋白质。PTHrP mRNA亚型表达的调节尚未完全阐明，但它可能受到转化生长因子β 1（TGF-β 1）的影响。在这项研究中，我们研究了PTHrP mRNA亚型表达的差异，在两个鳞状细胞癌细胞系（SCC 2/88和HARA），永生化角质形成细胞系（HaCaT），和自发性人肺癌与相邻的正常组织。此外，还检测了TGF-β 1对PTHrP mRNA亚型表达和稳定性的影响。PTHrP mRNA亚型的细胞类型特异性表达发生在各种细胞系、正常人肺和永生化人角质形成细胞（HaCaT）之间。PTHrP亚型在正常肺组织和癌旁肺组织中的表达模式有明显改变。体外研究表明，TGF-β 1差异性地改变了PTHrP亚型的mRNA稳态水平和mRNA稳定性。蛋白质-RNA结合研究鉴定了与PTHrP同种型的3 '-UTR结合的不同蛋白质（139）和（141），这可能在PTHrP同种型之间的差异mRNA稳定性和对细胞因子的应答中是重要的。这些数据表明，PTHrP mRNA亚型存在细胞类型特异性表达，癌症进展期间正常调节的破坏可能部分与TGF-β 1诱导的PTHrP mRNA亚型表达和稳定性变化相关。
Parathyroid hormone-related protein (PTHrP) is a multifunctional protein that is often dysregulated in cancer. The human PTHrP gene is alternatively spliced into three isoforms, each with a unique 3'-untranslated region (3'-UTR), encoding 139, 173 and 141 amino acid proteins. The regulation of PTHrP mRNA isoform expression has not been completely elucidated, but it may be affected by transforming growth factor-beta1 (TGF-beta1). In this study, we examined differences in the PTHrP mRNA isoform expression in two squamous carcinoma cell lines (SCC2/88 and HARA), an immortalized keratinocyte cell line (HaCaT), and spontaneous human lung cancer with adjacent normal tissue. In addition, the effect of TGF-beta1 on PTHrP mRNA isoform expression and stability was examined. Cell-type specific expression of PTHrP mRNA isoforms occurred between the various cell lines, normal human lung, and immortalized human keratinocytes (HaCaT). PTHrP isoform expression pattern was significantly altered between normal lung tissue and the adjacent lung cancer. In vitro studies revealed that TGF-beta1 differentially altered the mRNA steady-state levels and mRNA stability of the PTHrP isoforms. Protein-RNA binding studies identified different proteins binding to the 3'-UTR of the PTHrP isoforms (139) and (141), which may be important in the differential mRNA stability and response to cytokines between the PTHrP isoforms. The data demonstrate that there is cell-type specific expression of PTHrP mRNA isoforms, and disruption of the normal regulation during cancer progression may in part be associated with TGF-beta1-induced changes in PTHrP mRNA isoform expression and stability.