Alternative splicing to exon 11 of human prolactin receptor gene results in multiple isoforms including a secreted prolactin-binding protein
Alternative splicing to exon 11 of human prolactin receptor gene results in multiple isoforms including a secreted prolactin-binding protein
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DOI：
10.1677/jme.0.0300031
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发表时间：
2003-02-01
影响因子：
3.5
通讯作者：
Vonderhaar, BK
中科院分区：
文献类型：
--
作者：
Trott, JF;Hovey, RC;Vonderhaar, BK
内分泌和自分泌催乳素（PRL）对正常乳腺和乳腺癌细胞有影响，高血清PRL是结直肠癌预后不良的因素。在这里，我们测试的假设，短亚型的催乳素受体（PRLR）在人体组织调节催乳素在癌症中的行动。使用3' RACE，我们分离了人PRLR（hPRLR）的五种剪接变体，其中三种编码完整的细胞外结合结构域。其中两种亚型，短型1a（SF 1a）和短型1b（SF 1b），具有独特的细胞内结构域，分别由外显子10和9剪接到外显子11编码。第三种新的同种型（Delta 7/11）反映了从外显子7到外显子11的选择性剪接，并编码分泌的可溶性PRL结合蛋白。还鉴定了缺少外显子4的SF 1b和Delta 7/11的其他剪接变体（Delta 4-SF 1b和A4-Delta 7/11）。功能分析表明，hPRLR-SF 1b是一个强显性负的PRLR长型的分化功能，而hPRLR-SF 1a是一个较弱的显性负。在正常乳腺、结肠、胎盘、肾脏、肝脏、卵巢和胰腺以及乳腺和结肠肿瘤中检测到SF 1a、SF 1b和Delta 7/11表达的差异丰度。总而言之，这些数据表明hPRLR的多种亚型的存在，它们可能具有调节正常人体组织和癌症中PRL的内分泌和自分泌作用的功能。
Endocrine and autocrine prolactin (PRL) exerts effects on normal breast and breast cancer cells, and high serum PRL is a poor prognostic factor for colorectal cancer. Here we tested the hypothesis that short isoforms of the PRL receptor (PRLR) in human tissue regulate the actions of PRL in cancer. Using 3' RACE we isolated five splice variants of the human PRLR (hPRLR), three of which encode the complete extracellular binding domain. Two of these isoforms, short form 1a (SF1a) and short form 1b (SF1b), possess unique intracellular domains encoded by splicing to exon 11 from exons 10 and 9 respectively. A third novel isoform (Delta7/11) reflects alternative splicing from exon 7 to exon 11 and encodes a secreted soluble PRL-binding protein. Additional splice variants of SF1b and Delta7/11 that lacked exon 4 (Delta4-SF1b and A4-Delta7/11) were also identified. Functional analyses indicated that hPRLR-SF1b is a strong dominant-negative to the differentiative function of the PRLR long form while hPRLR-SF1a is a weaker dominant-negative. Differential abundance of SF1a, SF1b and Delta7/11 expression was detected in normal breast, colon, placenta, kidney, liver, ovary and pancreas, and breast and colon tumors. Taken together, these data indicate the presence of multiple isoforms of the hPRLR that may function to modulate the endocrine and autocrine effects of PRL in normal human tissue and cancer.