Requirement for phosphatidylinositol 3'-kinase to protect hemopoietic progenitors against apoptosis depends upon the extracellular survival factor.
Requirement for phosphatidylinositol 3'-kinase to protect hemopoietic progenitors against apoptosis depends upon the extracellular survival factor.
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DOI：
10.4049/jimmunol.156.3.939
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发表时间：
1996-02
影响因子：
4.4
通讯作者：
C. Minshall;S. Arkins;S. Arkins;G. Freund;K. Kelley
中科院分区：
文献类型：
--
作者：
C. Minshall;S. Arkins;S. Arkins;G. Freund;K. Kelley
造血生长因子通过防止祖细胞凋亡促进祖细胞存活。最近，磷脂酰肌醇3 '-激酶（PI 3-激酶）已被证明是胰岛素和神经生长因子防止细胞凋亡的途径中不可或缺的。在这项工作中，我们表明，IL-3依赖性FDCP-1/Mac-1小鼠造血祖细胞表达受体的另一种生长因子，胰岛素样生长因子-I（IGF-I），IL-3和IGF-I刺激PI 3-激酶活性。然后，我们证明IGF-I与IL-3共享显著促进骨髓祖细胞增殖和增强存活的特性，浓度低至3 ng/ml。IL-3和IGF-I在RNA合成（放线菌素D）或有丝分裂（丝裂霉素C）抑制剂存在下有效促进细胞存活，表明两种配体通过在很大程度上独立于RNA合成的过程促进存活。为了确定PI 3-激酶是否介导IL-3和IGF-I诱导的细胞凋亡抑制，将FDCP-1/Mac-1细胞与PI 3-激酶抑制剂渥曼青霉素一起孵育。虽然渥曼青霉素抑制基础和IGF-I和IL-3诱导的PI 3激酶活性，但它不影响IL-3保护FDCP-1/Mac-1细胞免于凋亡的能力，即使它消除了IGF-I诱导的凋亡抑制。这些数据表明，即使PI 3-激酶的激活是髓系祖细胞中IL-3和IGF-I受体的多效性特征，但IL-3而不是IGF-I对凋亡的预防不依赖于PI 3-激酶。因此，造血祖细胞的存活通过至少两种不同的细胞内信号传导途径维持，一种需要PI 3-激酶，另一种不需要。
Hemopoietic growth factors promote survival of progenitor cells by preventing their apoptotic death. Recently, phosphatidylinositol 3'-kinase (PI 3-kinase) has been shown to be integral in the pathway by which insulin and nerve growth factor prevent apoptosis. In this work, we show that IL-3-dependent FDCP-1/Mac-1 murine hemopoietic progenitors express receptors for another growth factor, insulin-like growth factor-I (IGF-I), and that both IL-3 and IGF-I stimulate PI 3-kinase activity. We then demonstrate that IGF-I shares with IL-3 the properties of significantly promoting proliferation and enhancing survival of myeloid progenitor cells at concentrations as low as 3 ng/ml. IL-3 and IGF-I efficiently promote cell survival in the presence of inhibitors of either RNA synthesis (actinomycin D) or mitosis (mitomycin C), suggesting that both ligands promote survival by a process that is largely independent of RNA synthesis. To determine whether PI 3-kinase mediates IL-3- and IGF-I-induced inhibition of apoptosis, FDCP-1/Mac-1 cells were incubated with the PI 3-kinase inhibitor, wortmannin. While wortmannin inhibited both basal and IGF-I- and IL-3-induced PI 3-kinase enzyme activity, it did not affect the ability of IL-3 to protect FDCP-1/Mac-1 cells from apoptosis, even though it abrogated the IGF-I-induced inhibition of apoptosis. These data demonstrate that even though activation of PI 3-kinase is a pleiotropic feature of both IL-3 and IGF-I receptors in myeloid progenitors, prevention of apoptosis by IL-3 but not IGF-I is independent of PI 3-kinase. Survival of hemopoietic progenitors is therefore maintained by at least two different intracellular signaling pathways, one requiring PI 3-kinase and one that does not.