Growth hormone (GH)-stimulated insulin-like growth factor I gene expression is mediated by a tyrosine phosphorylation pathway depending on C-terminal region of human GH receptor in human GH receptor-expressing Ba/F3 cells.
Growth hormone (GH)-stimulated insulin-like growth factor I gene expression is mediated by a tyrosine phosphorylation pathway depending on C-terminal region of human GH receptor in human GH receptor-expressing Ba/F3 cells.
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DOI：
10.1210/en.2003-0811
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发表时间：
2004
期刊：
影响因子：
4.8
通讯作者：
H. Yoshizato;Minoru Tanaka;N. Nakai;N. Nakao;K. Nakashima
中科院分区：
文献类型：
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作者：
H. Yoshizato;Minoru Tanaka;N. Nakai;N. Nakao;K. Nakashima
尽管已有研究表明Janus激酶（JAK）-信号转导和转录激活因子（STAT）5 b通路在肝脏IGF-1表达中起重要作用，但GH刺激IGF-1基因表达的信号通路仍不清楚。本研究在稳定表达人GH受体的小鼠pro-B，Ba/F3细胞（Ba/F3-hGHR）中检测了GH依赖性IGF-I基因的表达及其细胞内信号转导机制。在Ba/F3-hGHR细胞中，人GH（0.01-10 nm）以剂量依赖性方式刺激IGF-I基因表达。JAK 2特异性抑制剂显著抑制GH诱导的IGF-I基因表达，但MAPK或磷脂酰肌醇3激酶特异性抑制剂未能阻断GH对IGF-I基因表达的刺激。然而，genistein，一种不抑制JAK 2和STAT 5磷酸化的非特异性酪氨酸激酶抑制剂，显著抑制GH诱导的IGF-I基因表达。此外，含有截短的C-末端hGHR直至D351的Ba/F3-hGHR突变体在响应人GH时未显示IGF-I基因表达。D351型通常具有GH诱导的JAK/STAT 5酪氨酸磷酸化。这些结果表明JAK-STAT 5通路和新的酪氨酸磷酸化通路依赖于来自hGHR C端区域的信号传导，可能参与GH刺激的Ba/F3细胞中IGF-I基因表达。
The signaling pathway of GH-stimulated IGF-I gene expression is still unclear, although it has been reported that the Janus kinase (JAK)-signal transducers and activators of transcription (STAT)5b pathway plays an important role in liver IGF-I expression. In this study, the GH-dependent IGF-I gene expression and its intracellular signaling mechanism have been examined in mouse pro-B, Ba/F3 cells stably expressing human GH receptor (Ba/F3-hGHR). The IGF-I gene expression was stimulated by human GH (0.01-10 nm) in a dose-dependent fashion in Ba/F3-hGHR cells. The specific inhibitors for JAK2 remarkably suppressed the GH-induced IGF-I gene expression, but MAPK or phosphatidylinositol 3 kinase-specific inhibitors failed to block the GH stimulation of the IGF-I gene expression. However, genistein, a nonspecific tyrosine kinase inhibitor that does not inhibit JAK2 and STAT5 phosphorylation, significantly suppressed the GH-induced IGF-I gene expression. Additionally, a Ba/F3-hGHR mutant that contained the truncated C-terminal hGHR up to D351 showed no IGF-I gene expression in response to human GH. The D351 form normally has the GH-induced JAK/STAT5 tyrosine phosphorylation. These results suggest that the JAK-STAT5 pathway and the novel tyrosine phosphorylation pathway, dependent on signaling from the C-terminal region of hGHR, might be involved in the GH-stimulated IGF-I gene expression in Ba/F3 cells.