Tumor-specific expression and alternate splicing of messenger ribonucleic acid encoding activin/transforming growth factor-beta receptors in human pituitary adenomas.
Tumor-specific expression and alternate splicing of messenger ribonucleic acid encoding activin/transforming growth factor-beta receptors in human pituitary adenomas.
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DOI：
10.1210/jcem.81.2.8636304
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发表时间：
1996-02
期刊：
影响因子：
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通讯作者：
J. M. Alexander;H. Bikkal;N. Zervas;E. R. Laws;A. Klibanski
中科院分区：
文献类型：
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作者：
J. M. Alexander;H. Bikkal;N. Zervas;E. R. Laws;A. Klibanski
激活素是转化生长因子β（TGF β）细胞因子家族的成员，通过受体连接的丝氨酸/苏氨酸（Ser/Thr）激酶的新家族作为垂体细胞有丝分裂原起作用。垂体瘤合成激活素亚单位，这些生长因子的自分泌作用可调节肿瘤增殖。因此，我们研究了激活素/TGF β I型受体信使核糖核酸（mRNA）的表达，命名为ALK 1至ALK 5（ALK =激活素受体样激酶），和II型受体mRNA使用RT-PCR在34人垂体腺瘤的所有表型和正常垂体组织。ALK 2和ALK 5分别是激活素和TGF β信号的特异性介质，仅在肿瘤中表达，而在正常垂体细胞中不表达，ALK 2仅在乳腺生长激素细胞系的肿瘤中表达。ALK 1、ALK 3和ALK 4 mRNA在正常和肿瘤垂体细胞中均被发现。ALK 4的可变剪接胞质结构域由11个激酶亚结构域组成，这些亚结构域对于调节受体功能和细胞内信号传导至关重要。缺乏这些亚结构域的ALK 4胞质结构域的截短形式可能减弱激活素信号转导，并通过形成无活性的I型/II型复合物影响肿瘤表型和增殖。通过细胞质Ser/Thr激酶结构域的选择性剪接产生的三种截短的ALK 4受体mRNA被发现具有肿瘤特异性。这些截短的受体mRNA之一，ALK 4 -5，是一种新的剪接变体，以前没有描述过。ActRII和T β RII II II型受体mRNA的表达，分别特异性结合激活素和TGF β，在所有肿瘤亚型和正常垂体组织中非常普遍。然而，ActRIIB，一种激活素特异性II型受体，显示出比ActRII高3至4倍的配体亲和力，在94%的肿瘤中表达，但在正常组织中不普遍。这些数据是第一个证明肿瘤特异性表达的丝氨酸/苏氨酸激酶受体mRNA及其剪接变异体在人类垂体腺瘤。
Activin, a member of the transforming growth factor-beta (TGF beta) cytokine family, acts as a pituitary cell mitogen via a novel family of receptor-linked serine/threonine (Ser/Thr) kinases. Pituitary tumors synthesize activin subunits, and the autocrine action of these growth factors may modulate tumor proliferation. We, therefore, investigated the expression of activin/TGF beta type I receptor messenger ribonucleic acids (mRNAs), designated ALK1 through ALK5 (ALK = activin receptor-like kinase), and type II receptor mRNAs using RT-PCR in 34 human pituitary adenomas of all phenotypes and normal pituitary tissue. ALK2 and ALK5, specific mediators of activin and TGF beta signals, respectively, were found to be expressed only in tumor and not in normal pituitary cells, and ALK2 expression was found only in tumors of a mammosomatotroph cell lineage. ALK1, ALK3, and ALK4 mRNAs were found in both normal and neoplastic pituitary cells. The alternatively spliced cytoplasmic domain of ALK4 consists of 11 kinase subdomains, that are critical for modulating receptor function and intracellular signaling. Truncated forms of the ALK4 cytoplasmic domain lacking these subdomains may attenuate activin signal transduction and affect both tumor phenotype and proliferation via the formation of inactive type I/type II complexes. Three truncated ALK4 receptor mRNAs generated by alternate splicing of the cytoplasmic Ser/Thr kinase domain were found to be tumor specific. One of these truncated receptor mRNAs, ALK4-5, is a novel splice variant that has not been previously described. Expression of the ActRII and T beta RII type II receptor mRNAs, which specifically bind activin and TGF beta, respectively, was highly prevalent among all tumor subtypes and normal pituitary tissue. However, ActRIIB, an activin-specific type II receptor that displays a 3- to 4-fold higher affinity for ligand than ActRII, was expressed in 94% of tumors, but was not prevalent in normal tissue. These data are the first to demonstrate tumor-specific expression of Ser/Thr kinase receptors mRNAs and their splice variants in human pituitary adenomas.