共查询到20条相似文献,搜索用时 15 毫秒
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Siew Hwey Tan Mintu Pal Ming Jie Tan Marc Hai Liang Wong Fong U. Tam Jamie Wei Ting Teo Han Chung Chong Chek Kun Tan Yan Yih Goh Mark Boon Yang Tang Peter Ching For Cheung Nguan Soon Tan 《The Journal of biological chemistry》2009,284(27):18047-18058
Skin maintenance and healing after wounding requires complex epithelial-mesenchymal interactions purportedly mediated by growth factors and cytokines. We show here that, for wound healing, transforming growth factor-β-activated kinase 1 (TAK1) in keratinocytes activates von Hippel-Lindau tumor suppressor expression, which in turn represses the expression of platelet-derived growth factor-B (PDGF-B), integrin β1, and integrin β5 via inhibition of the Sp1-mediated signaling pathway in the keratinocytes. The reduced production of PDGF-B leads to a paracrine-decreased expression of hepatocyte growth factor in the underlying fibroblasts. This TAK1 regulation of the double paracrine PDGF/hepatocyte growth factor signaling can regulate keratinocyte cell proliferation and is required for proper wound healing. Strikingly, TAK1 deficiency enhances cell migration. TAK1-deficient keratinocytes displayed lamellipodia formation with distinct microspike protrusion, associated with an elevated expression of integrins β1 and β5 and sustained activation of cdc42, Rac1, and RhoA. Our findings provide evidence for a novel homeostatic control of keratinocyte proliferation and migration mediated via TAK1 regulation of von Hippel-Lindau tumor suppressor. Dysfunctional regulation of TAK1 may contribute to the pathology of non-healing chronic inflammatory wounds and psoriasis.Wound healing is a highly dynamic process that involves complex interactions of extracellular matrix molecules, soluble mediators, various resident cells, and infiltrating leukocyte subtypes. The immediate goal in repair is to achieve tissue integrity and homeostasis. The healing process involves three phases that overlap in time and space, namely inflammation, re-epithelialization, and tissue remodeling. Re-epithelialization is accomplished by increased keratinocyte proliferation and guided migration of the keratinocytes over the granulation tissue. Such processes require ordered changes in keratinocyte behavior and phenotype, which are dictated by the interplay of keratinocytes with dermal fibroblasts, i.e. epithelial-mesenchymal communication. This complex interplay demands the integration of diverse signals through a network of soluble factors exerting autocrine and paracrine activity from the wound microenvironment, culminating in appropriate cellular responses (1, 2). Aberrations to this signaling network may impair or enhance cell migration and proliferation, leading to insufficient or excessive wound repair and life-threatening consequences such as tumor growth and metastasis. Therefore, to understand the effect of any molecule in normal cellular function, studies into its role in this signaling network and how they culminate to an appropriate cell response become fundamental and necessary.Transforming growth factor-β (TGF-β)4-activated kinase 1 (TAK1) belongs to the MAPK kinase kinase family. This serine/threonine kinase is a key intermediate in inflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin 1 (IL-1) (3, 4) as well as TGF-β (5)-mediated signaling pathways. Activated TAK1 has the capacity to stimulate its downstream MAPK and NFκB-inducing kinase-IκB kinase cascades (6). The former activates c-Jun N-terminal kinase (JNK) and p38 MAPK while the latter activates NF-κB (3, 7, 8). A deficiency in TAK1 results in impaired TNF-α- and IL-1-stimulated JNK activity, p38 phosphorylation, and IκBα degradation (7, 9). Studies of keratinocyte-specific TAK1 knock-out (TAK1-KO) mice confirmed the role of TAK1 in skin inflammation. These TAK1-KO mice died by postnatal day 7 and developed intra-epidermal micro-abscesses (10, 11). The TAK1-KO mice displayed abnormal epidermis with impaired differentiation and increased cellular proliferation; however, no significant difference in proliferation index was observed in culture of these mutant keratinocytes in vitro. Nevertheless, the latter suggests a crucial role of the underlying dermis in mitigating some effects of epidermal TAK1. Although the role of TAK1 in inflammatory response is well established, the role of TAK1 and its mechanism of action in keratinocyte proliferation and migration remain unknown.Herein, we show that the deficiency in TAK1 resulted in increased cell proliferation and migration. We provide evidence of a double paracrine mechanism that make a pivotal contribution to the enhanced cell proliferation in TAK1-deficient epidermis. This study also reveals a novel homeostatic role of TAK1 in controlling cell migration. These aberrant phenotypes, as a consequence of TAK1 deficiency, are mediated via the dysregulated expression of von Hippel-Lindau tumor suppressor. 相似文献
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《Autophagy》2013,9(3):171-173
Autophagy was recently established as a novel tumor suppression mechanism, which stimulated a wave of investigations that were aimed at understanding exactly how autophagy prevents tumorigenesis, as well as to determine to what extent autophagy is implicated in human cancers. Autophagy might exert its tumor suppression function at the subcellular level by removing defective cytoplasmic components, such as damaged mitochondria. In addition, it might function at the cellular level by helping in the orderly removal of damaged cells. Previous studies indicated that autophagy is compromised in human breast, ovarian and prostate cancers. Recent research revealed that autophagy is activated by p53, a critical tumor suppressor that is involved in most, if not all, tumorigenesis. This study places autophagy in a broader context of human cancers. Future work elucidating the role of autophagy in the p53 circuit and p53 function might provide more insight into tumorigenesis and targeted cancer chemotherapy. 相似文献
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Yanfen Hu 《International journal of biological sciences》2009,5(1):20-27
Germline mutations of BRCA1 predispose women to breast and ovarian cancers. Elucidating molecular mechanism of tissue- and gender-specific phenomena in BRCA1-related tumors is a key to our understanding of BRCA1 function in tumor suppression. This review summarizes studies in recent years on the link between BRCA1 and estrogen/progesterone signaling pathways, as well as discusses various models underscoring a triangle relationship among BRCA1, estrogen and genome instability. 相似文献
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Hiroki Takeshita Atsushi Shiozaki Xiao-Hui Bai Daisuke Iitaka Hyunhee Kim Burton B. Yang Shaf Keshavjee Mingyao Liu 《PloS one》2013,8(3)
XB130, a novel adaptor protein, promotes cell growth by controlling expression of many related genes. MicroRNAs (miRNAs), which are frequently mis-expressed in cancer cells, regulate expression of targeted genes. In this present study, we aimed to explore the oncogenic mechanism of XB130 through miRNAs regulation. We analyzed miRNA expression in XB130 short hairpin RNA (shRNA) stably transfected WRO thyroid cancer cells by a miRNA array assay, and 16 miRNAs were up-regulated and 22 miRNAs were down-regulated significantly in these cells, in comparison with non-transfected or negative control shRNA transfected cells. We chose three of the up-regulated miRNAs (miR-33a, miR-149 and miR-193a-3p) and validated them by real-time qRT-PCR. Ectopic overexpression of XB130 suppressed these 3 miRNAs in MRO cells, a cell line with very low expression of XB130. Furthermore, we transfected miR mimics of these 3 miRNAs into WRO cells. They negatively regulated expression of oncogenes (miR-33a: MYC, miR-149: FOSL1, miR-193a-3p: SLC7A5), by targeting their 3′ untranslated region, and reduced cell growth. Our results suggest that XB130 could promote growth of cancer cells by regulating expression of tumor suppressive miRNAs and their targeted genes. 相似文献
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人内皮生长抑制素基因克隆表达及其抑瘤作用 总被引:6,自引:3,他引:6
内皮生长抑制素(endostatin是最近报道具有抑制肿瘤生长和铁蛋白质,为此,从正常人肝细胞株L02中抽提总RNA,以RT-PCR法获得了人内皮生长抑制素编码序列,序列分析表明,内皮生长抑制素CDNA开放阅读框架全长555bp,此基因(GenBank登录号为A地84060),共编码1、84个氨基酸残序列为5个碱基与文献报道不同,蛋白质序列中有3个氨基酸残基与文献报道不同,说明存在人种间差异。将人 相似文献
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肿瘤抑制基因Rb与细胞周期调控研究新进展 总被引:10,自引:0,他引:10
Rb与人类多种肿瘤发生关系密切,是一种重要的肿瘤抑制基因.Rb蛋白参与细胞周期调控,与p16、CDK4/6、cyclinD1等形成复杂的反馈调节网络,在G1/S关卡调控中处于中心环节,决定着细胞周期的进程.Rb又是核内信号与胞外信号相互作用的界面,受到胞内外多种因素的调控,使Rb功能与细胞生长、分化状态相适应. 相似文献
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E2F是一个重要的转录因子家族,通过调节靶基因的转录活性在细胞周期、DNA复制、生长、分化、凋亡等多种细胞进程中发挥关键的作用.转录因子家族DP与E2F结合形成E2F/DP异二聚体,对E2F的DNA结合亲和力和转录激活功能起到增强的作用,是生理状态下E2F必不可少的组成部分.DP蛋白家族有三个成员,即DP-1、DP-2和DP-3,其中DP-1具有三个异构体,DP-2具有四个异构体.DP蛋白家族成员以及异构体间存在结构和功能的差异,能通过组织特异性表达和显性负性方式在家族内部构成调节系统,对生理功能进行精细调节.E2F-1兼具抑癌和促癌双重作用,已得到人们的广泛关注.DP蛋白作为E2F的结合伴侣对其功能起到重要的调节作用,加之以DP-3在肿瘤细胞中的特异性表达,提示DP蛋白与肿瘤间存在密切的关系.本文就此将近年来的研究成果进行总结,并提出进一步研究的设想. 相似文献