Murine embryonic stem cell differentiation is promoted by SOCS-3 and inhibited by the zinc finger transcription factor Klf4
Murine embryonic stem cell differentiation is promoted by SOCS-3 and inhibited by the zinc finger transcription factor Klf4
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DOI：
10.1182/blood-2004-07-2681
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发表时间：
2005-01-15
期刊：
影响因子：
20.3
通讯作者：
Chan, RJ
中科院分区：
文献类型：
--
作者：
Li, Y;McClintick, J;Chan, RJ
Shp-2突变（Shp-2（Delta 46 -110））纯合的胚胎干（ES）细胞表现出白血病抑制因子（LIF）超敏性和LIF刺激的信号转导和转录激活因子（STAT 3）磷酸化增加。我们假设Shp-2（Delta 46 -110）细胞中的LIF反应基因将代表对ES细胞自我更新至关重要的分子的潜在候选者。利用微阵列分析，我们检测到41个基因的表达被LIF修饰的Shp-2（Delta 46 -110）ES细胞。采用北方印迹法验证了2个显著上调基因的诱导，即细胞因子信号传导抑制因子-3（SOCS-3）和Kruppel样因子4（Klf 4）。过表达SOCS-3的ES细胞分化为造血祖细胞的能力增加，而不是自我更新。相反，过表达Klf 4的ES细胞具有更大的基于次生胚状体（EB）形成的自我更新能力。Klf 4转导的d 6 EB表达更高水平的Oct-4。这与Klf 4促进ES细胞自我更新的观点一致。这些发现证实了SOCS-3对LIF信号的负作用，并为Klf 4在ES细胞功能中提供了新的作用。
Embryonic stem (ES) cells homozygous for a Shp-2 mutation (Shp-2(Delta46-110)) demonstrate leukemia inhibitory factor (LIF) hypersensitivity and increased LIF-stimulated phosphorylation of signal transducer and activator of transcription (STAT3). We hypothesized that LIF-responsive genes in Shp-2(Delta46-110) cells would represent potential candidates for molecules vital for ES cell self-renewal. Using microarray analysis, we detected 41 genes whose expression was modified by LIF in Shp-2(Delta46-110) ES cells. Induction of 2 significantly up-regulated genes, suppressor of cytokine signaling-3 (SOCS-3) and Kruppel-like factor 4 (Klf4), was verified using Northern blotting. ES cells overexpressing SOCS-3 had an increased capacity to differentiate to hematopoietic progenitors, rather than to self-renew. In contrast, ES cells overexpressing Klf4 had a greater capacity to self-renew based on secondary embryoid body (EB) formation. Klf4-transduced d6 EBs expressed higher levels of Oct-4. consistent with the notion that Klf4 promotes ES cell self-renewal. These findings verity the negative role of SOCS-3 on LIF signaling and provide a novel role for Klf4 in ES cell function.