Insulinlike growth factor-I signaling in multiple myeloma: downstream elements, functional correlates, and pathway cross-talk
Insulinlike growth factor-I signaling in multiple myeloma: downstream elements, functional correlates, and pathway cross-talk
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DOI：
10.1182/blood.v99.11.4138
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发表时间：
2002-06-01
期刊：
影响因子：
20.3
通讯作者：
Rudikoff, S
中科院分区：
文献类型：
--
作者：
Qiang, YW;Kopantzev, E;Rudikoff, S
在多发性骨髓瘤细胞中，胰岛素样生长因子-I(IGF-I)激活两条不同的信号通路，即丝裂原活化蛋白激酶(MAPK)和磷脂酰肌醇3-激酶(PI-3K)，导致增殖和抗凋亡作用。然而，目前还不清楚IGF-I通过这些级联反应中的哪一个来调节这些不同的反应。目前的研究发现了PI-3K途径的一系列下游靶点，包括糖原合成酶激酶-3β、p70S6激酶以及Forkhead转录因子家族的3个成员。MAPK和PI-3K通路的作用，以及在可能的情况下，单个元件在增殖和凋亡中的作用通过一系列特定的激酶抑制剂进行评估。这两个过程几乎完全受PI-3K通路的调控，与MAPK级联反应相关的贡献很小。在PI-3K级联反应中，抑制p70S6激酶可显著抑制细胞增殖并保护其免受细胞凋亡的影响。MAPK抑制剂也可以阻止p70S6激酶的激活，这表明这两个途径都有调节作用。Forkhead转录因子FKHRL1被观察到提供双重作用，因为IGF-I处理时的磷酸化导致失去抑制增殖和诱导凋亡的能力。此外，PI-3K通路还表现出串扰并调节MAPK级联反应，因为抑制PI-3K可以阻止MEK1/2和其他下游MAPK元件的激活。这些结果确定了IGF-I调控骨髓瘤细胞生长的重要因素，并提供了对理解生长因子对增殖和凋亡的调控至关重要的生物学关联。(C)2002年，由美国血液病学会公布。
In multiple myeloma cells, insulinlike growth factor-I (IGF-I) activates 2 distinct signaling pathways, mitogen-activated protein kinase (MAPK) and phosphoinositol 3-kinase (PI-3K), leading to both proliferative and antiapoptotic effects. However, it is unclear through which of these cascades IGF-I regulates these different responses. The present studies identify a series of downstream targets in the PI-3K pathway, including glycogen synthase kinase-3beta, p70S6 kinase, and the 3 members of the Forkhead family of transcription factors. The contribution of the MAPK and PI-3K pathways and, where possible, individual elements to proliferation and apoptosis was evaluated by means of a series of specific kinase inhibitors. Both processes were regulated almost exclusively by the PI-3K pathway, with only minor contributions associated with the MAPK cascade. Within the PI-3K cascade, inhibition of p70S6 kinase led to significant decreases in proliferation and protection from apoptosis. Activation of p70S6 kinase could also be prevented by MAPK inhibitors, Indicating regulation by both pathways. The Forkhead transcription factor FKHRL1 was observed to provide a dual effect in that phosphorylation upon IGF-I treatment resulted In a loss of ability to Inhibit proliferation and Induce apoptosis. The PI-3K pathway was additionally shown to exhibit cross-talk and to regulate the MAPK cascade, as Inhibition of PI-3K prevented activation of Mek1/2 and other downstream MAPK elements. These results define Important elements In IGF-I regulation of myeloma cell growth and provide biological correlates critical to an understanding of growth-factor modulation of proliferation and apoptosis. (C) 2002 by The American Society of Hematology.