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Bone morphogenetic protein-2 (BMP-2), a member of transforming growth factor-beta superfamily, plays a crucial role in migration and metastasis of human cancer cells. Integrins are the major adhesive molecules in mammalian cells. Here we found that BMP-2 directed the migration and increased cell surface and mRNA expression of beta1 integrin in human chondrosarcoma cancer cells (JJ012). Pretreated of JJ012 cells with phosphatidylinositol 3-kinase inhibitor (PI3K; Ly294002) or Akt inhibitor inhibited the BMP-2-mediated migration and integrin expression. BMP-2 increased the phosphorylation of p85 subunit of PI3K and serine 473 of Akt. In addition, NF-kappaB inhibitor (PDTC) or IkappaB protease inhibitor (TPCK) also inhibited BMP-2-mediated cells migration and integrin upregulation. Stimulation of JJ012 cells with BMP-2 induced IkappaB kinase (IKKalpha/beta) phosphorylation, IkappaB phosphorylation, p65 Ser(536) phosphorylation, and kappaB-luciferase activity. Furthermore, the BMP-2-mediated increasing of IKKalpha/beta phosphorylation, IkappaB phosphorylation, and p65 Ser(536) phosphorylation were inhibited by Ly294002 and Akt inhibitor. Co-transfection with p85 and Akt mutants also reduced the BMP-2-induced kappaB-luciferase activity. Taken together, these results suggest that the BMP-2 acts through PI3K/Akt, which in turn activates IKKalpha/beta and NF-kappaB, resulting in the activations of beta1 integrin and contributing the migration of human chondrosarcoma cells.  相似文献   

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WTX encodes a tumor suppressor, frequently inactivated in Wilms tumor, with both plasma membrane and nuclear localization. WTX has been implicated in β-catenin turnover, but its effect on nuclear proteins is unknown. We report an interaction between WTX and p53, derived from the unexpected observation of WTX, p53, and E1B 55K colocalization within the characteristic cytoplasmic body of adenovirus-transformed kidney cells. In other cells without adenovirus expression, the C-terminal domain of WTX binds to the DNA-binding domain of p53, enhances its binding to CBP, and increases CBP/p300-mediated acetylation of p53 at Lys 373/382. WTX knockdown accelerates CBP/p300 protein turnover and attenuates this modification of p53. In p53-reconstitution experiments, cell-cycle arrest, apoptosis, and p53 target-gene expression are suppressed by depletion of WTX. Together, these results suggest that WTX modulates p53 function, in part through regulation of its activator CBP/p300.  相似文献   

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The processing of the nfkappab2 gene product p100 to generate p52 is a regulated event, which is important for the instrumental function of NF-kappaB. We previously demonstrated that this tightly controlled event is regulated positively by NF-kappaB-inducing kinase (NIK) and its downstream kinase, IkappaB kinase alpha (IKKalpha). However, the precise mechanisms by which NIK and IKKalpha induce p100 processing remain unclear. Here, we show that, besides activating IKKalpha, NIK also serves as a docking molecule recruiting IKKalpha to p100. This novel function of NIK requires two specific amino acid residues, serine 866 and serine 870, of p100 that are known to be essential for inducible processing of p100. We also show that, after being recruited into p100 complex, activated IKKalpha phosphorylates specific serines located in both N- and C-terminal regions of p100 (serines 99, 108, 115, 123, and 872). The phosphorylation of these specific serines is the prerequisite for ubiquitination and subsequent processing of p100 mediated by the beta-TrCP ubiquitin ligase and 26 S proteasome, respectively. These results highlight the critical but different roles of NIK and IKKalpha in regulating p100 processing and shed light on the mechanisms mediating the tight control of p100 processing. These data also provide the first evidence for explaining why overexpression of IKKalpha or its activation by many other stimuli such as tumor necrosis factor and mitogens fails to induce p100 processing.  相似文献   

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Liang C  Zhang M  Sun SC 《Cellular signalling》2006,18(8):1309-1317
Processing of the NF-kappaB2 precursor protein p100 is a major step in noncanonical NF-kappaB signaling. This signaling step requires the NF-kappaB inducing kinase (NIK) and its downstream kinase, IkappaB kinase alpha (IKKalpha). We show here that p100 undergoes phosphorylation at serines 866, 870, and possibly 872, in cells stimulated with noncanonical NF-kappaB stimuli or transfected with NIK and IKKalpha. Phosphorylation of this serine cluster creates a binding site for beta-TrCP, the receptor subunit of the beta-TrCP(SCF) ubiquitin ligase. Mutation of either serine 866 or serine 870 abolishes the beta-TrCP recruitment and ubiquitination of p100. The functional significance of p100 phosphorylation is further supported by the finding that this molecular event occurs in a NIK- and IKKalpha-dependent manner. Additionally, induction of p100 phosphorylation can be blocked by a protein synthesis inhibitor, suggesting the requirement of de novo protein synthesis. These data suggest that p100 processing involves its phosphorylation at specific terminal serines, which form a binding site for beta-TrCP thereby regulating p100 ubiquitination.  相似文献   

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Transcriptional cross talk between NF-kappaB and p53   总被引:11,自引:0,他引:11       下载免费PDF全文
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The human immunodeficiency virus (HIV) transactivating Tat protein is not only critical for viral replication but also affects the host immune system by inducing the production of cytokines such as IL-10. This anti-inflammatory cytokine is upregulated during the course of HIV infection, representing an important pathway by which HIV may induce immunodeficiency. Here, we show that, by acting at the membrane, Tat induces IL-10 expression in primary monocytes and promonocytic U937 cells by NF-kappaB-dependent pathways. The trans-dominant negative mutants of NF-kappaB-inducing kinase (NIK), IKKalpha and IKKbeta expressed in our transactivation model, in accordance with the nuclear binding of p65 and p52 NF-kappaB subunits to the IL-10 promoter, suggest the involvement of both classical and alternative NF-kappaB pathways. In inactivated cells, IKKalpha is localized predominantly in the cytoplasm. Interestingly, Tat stimulates IKKalpha translocation from the cytoplasm to the nucleus in monocytes. Chromatin immunoprecipitation (ChIP) assay experiments, after Tat treatment, revealed IKKalpha and CBP/p300 recruitment to the IL-10 promoter and histone H3 phosphorylation (Ser 10) and acetylation (Lys 14) in this region, presumably leading to chromatin remodeling. We demonstrate that, upstream of NF-kappaB, PKC, ERK1/2 and p38 MAP kinases are involved in Tat-induced IKKalpha nuclear translocation and histone H3 modifications on the IL-10 promoter in accordance with the role of these three kinases in IL-10 production. As a whole, the study demonstrates that Tat activates at least three signaling pathways concurrently, including the classical, alternative and IKKalpha pathways, to promote production of IL-10.  相似文献   

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