IKKα regulates mitogenic signaling through transcriptional induction of cyclin D1 via Tcf
IKKα regulates mitogenic signaling through transcriptional induction of cyclin D1 via Tcf
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DOI：
10.1091/mbc.02-06-0101
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发表时间：
2003-02-01
影响因子：
3.3
通讯作者：
Pestell, RG
中科院分区：
文献类型：
--
作者：
Albanese, C;Wu, KM;Pestell, RG
Wnt/β-连环蛋白/Tcf和IkappaB/NF-κ B级联是参与细胞周期控制、细胞分化和炎症的独立途径。组成性Wnt/β-连环蛋白信号传导发生在某些癌症中，来自该途径组分的突变和激活生长因子受体（包括罗恩和MET）。由此产生的细胞质和细胞核β-连环蛋白的积累与Tcf/LEF转录因子相互作用以诱导靶基因。使IkappaB磷酸化的IkappaB激酶复合物（IKK）含有IKK α、IKK β和IKK γ。在这里，我们表明，细胞周期蛋白D1基因的功能作为一个点之间的收敛Wnt/β-连环蛋白和IkappaB途径在有丝分裂信号。G1-S期进程和cyclin D1表达的促有丝分裂诱导是PI 3 K依赖的，cyclin D1（-/-）细胞显示PI 3 K依赖的S期进入减少。PI 3 K/Akt/IkappaB/IKK α或β-连环蛋白信号传导抑制剂可阻断PI 3 K依赖的细胞周期蛋白D1诱导。细胞周期蛋白D1启动子中的单个Tcf位点是PI 3 K或IKK α诱导所必需的。在IKK α（-/-）细胞中，丝裂原诱导的DNA合成和Tcf应答基因的表达减少。IKK α的重新引入通过Tcf位点恢复了正常的细胞周期蛋白D1的有丝分裂原诱导。在IKK α（-/-）细胞中，β-连环蛋白磷酸化降低，纯化的IKK α足以在体外通过其N-末端磷酸化β-连环蛋白。由于IKK α而不是IKK β通过Tcf活性诱导细胞周期蛋白D1的表达，这些研究表明，IKK α和IKK β的相对水平可能会改变其底物和信号特异性，通过不同的机制调节丝裂原诱导的DNA合成。
The Wnt/beta-catenin/Tcf and IkappaB/NF-kappaB cascades are independent pathways involved in cell cycle control, cellular differentiation, and inflammation. Constitutive Wnt/beta-catenin signaling occurs in certain cancers from mutation of components of the pathway and from activating growth factor receptors, including RON and MET. The resulting accumulation of cytoplasmic and nuclear beta-catenin interacts with the Tcf/LEF transcription factors to induce target genes. The IkappaB kinase complex (IKK) that phosphorylates IkappaB contains IKKalpha, IKKbeta, and IKKgamma. Here we show that the cyclin D1 gene functions as a point of convergence between the Wnt/beta-catenin and IkappaB pathways in mitogenic signaling. Mitogenic induction of G(1)-S phase progression and cyclin D1 expression was PI3K dependent, and cyclin D1(-/-) cells showed reduced PI3K-dependent S-phase entry. PI3K-dependent induction of cyclin D1 was blocked by inhibitors of PI3K/Akt/IkappaB/IKKalpha or beta-catenin signaling. A single Tcf site in the cyclin D1 promoter was required for induction by PI3K or IKKalpha. In IKKalpha(-/-) cells, mitogen-induced DNA synthesis, and expression of Tcf-responsive genes was reduced. Reintroduction of IKKalpha restored normal mitogen induction of cyclin D1 through a Tcf site. In IKKalpha(-/-) cells, beta-catenin phosphorylation was decreased and purified IKKalpha was sufficient for phosphorylation of beta-catenin through its N-terminus in vitro. Because IKKalpha but not IKKbeta induced cyclin D1 expression through Tcf activity, these studies indicate that the relative levels of IKKalpha and IKKbeta may alter their substrate and signaling specificities to regulate mitogen-induced DNA synthesis through distinct mechanisms.