IκB kinase-dependent chronic activation of NF-κB is necessary for p21WAF1/Cip1 inhibition of differentiation-induced apoptosis of monocytes
IκB kinase-dependent chronic activation of NF-κB is necessary for p21WAF1/Cip1 inhibition of differentiation-induced apoptosis of monocytes
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DOI：
10.1128/mcb.21.6.1930-1941.2001
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发表时间：
2001-03-01
影响因子：
5.3
通讯作者：
Paya, CV
中科院分区：
文献类型：
--
作者：
Pennington, KN;Taylor, JA;Paya, CV
调节单核细胞分化为巨噬细胞的分子机制仍然未知。虽然转录因子NF-κ B参与多种tell功能，但其在细胞分化中的作用不明确。由于分化的巨噬细胞，与循环的单核细胞相反，在细胞核中含有显著水平的NF-κ B，我怀疑这种转录因子是否参与巨噬细胞的分化。佛波醇12-肉豆蔻酸W-乙酸酯（PMA）诱导的前单核细胞系U937的分化导致持续的NF-κ B核转位我们在这里证明，IKK活性的增加和持续与单核细胞分化相关，导致持续的NF-kappaB激活，其次是通过I kappaB信号响应结构域（SRD）增加的I kappaB α降解。稳定过表达含有SRD突变的I κ B α转基因的前单核细胞不能激活NF-κ B，随后不能在PMA诱导的巨噬细胞分化程序中存活。分化诱导的细胞凋亡依赖于肿瘤坏死因子α。NF-κ B的保护作用是通过p21（WAF 1/Cip 1）介导的，因为发现这种蛋白质以NF-κ B依赖性方式调节，并在巨噬细胞分化期间赋予存活特征。因此，NF-κ B通过赋予细胞存活在细胞分化中起关键作用，在巨噬细胞的情况下，所述细胞存活通过p21（WAF 1/Cip 1）介导。
The molecular mechanisms regulating monocyte differentiation to macrophages remain unknown. Although the transcription factor NF-kappaB participates in multiple tell functions, its role in cell differentiation is ill defined. Since differentiated macrophages, in contrast to cycling monocytes, contain significant levels of NF-kappaB in the nuclei, me questioned whether this transcription factor is involved in macrophage differentiation. Phorbol 12-myristate W-acetate (PMA)-induced differentiation of the promonocytic cell line U937 leads to persistent NF-kappaB nuclear translocation. We demonstrate here that an increased and persistent IKK activity correlates with monocyte differentiation leading to persistent NF-kappaB activation secondary to increased I kappaB alpha degradation via the I kappaB signal response domain (SRD). Promonocytic cells stably overexpressing an I kappaB alpha transgene containing SRD mutations fail to activate NF-kappaB and subsequently fail to survive the PMA-induced macrophage differentiation program. The differentiation-induced apoptosis was found to be dependent on tumor necrosis factor alpha. The protective effect of NF-kappaB is mediated through p21(WAF1/Cip1), since this protein was found to be regulated in an NF-kappaB-dependent manner and to confer survival features during macrophage differentiation. Therefore, NF-kappaB plays a key role in cell differentiation by conferring cell survival that in the case of macrophages is mediated through p21(WAF1/Cip1).