Role of SAG/RBX2 E3 Ubiquitin Ligase in Skin Carcinogenesis
SAG/RBX2 E3 泛素连接酶在皮肤癌发生中的作用
基本信息
- 批准号:8785658
- 负责人:
- 金额:$ 32.27万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2013
- 资助国家:美国
- 起止时间:2013-01-03 至 2015-12-31
- 项目状态:已结题
- 来源:
- 关键词:Actinic keratosisAntineoplastic AgentsApoptosisApoptosis Inhibitor GeneCarcinogensCarcinoma in SituCell modelChemicalsChemopreventionDataDevelopmentDrug TargetingEmbryonic DevelopmentFutureGene SilencingGenesGeneticGoalsGrowthHealthHumanHuman DevelopmentHuman papillomavirus 16In VitroKnock-outKnockout MiceMAP Kinase GeneMalignant Epithelial CellMalignant NeoplasmsModelingMusNeurofibromatosis Type 1 ProteinPathway interactionsPharmacologic SubstancePhysical CarcinogensPhysiologicalPlayPreventionProteomicsPublishingRoleSkinSkin CancerSkin CarcinogenesisSkin NeoplasmsSkp1-Cullin-F-Box ProteinsSmall Interfering RNASquamous cell carcinomaStagingTeratomaTestingTissuesTranscription Factor AP-1Transgenic MiceTransgenic OrganismsTumor AngiogenesisUV inducedValidationViralViral OncogeneWorkangiogenesisantiangiogenesis therapybasecancer therapycancer viral etiologycarcinogenesischemical carcinogendimethylbenzanthraceneembryonic stem cellhuman FRAP1 proteinin vivoinhibitor/antagonistinnovationkeratinocyte differentiationmelanomamouse modelnoveloverexpressionskin squamous cell carcinomasmall moleculetargeted cancer therapytumortumorigenesisubiquitin-protein ligaseultraviolet irradiation
项目摘要
DESCRIPTION (provided by applicant): Targeted cancer therapy relies on thorough validation of cancer targets. Our long-range goal is to discover a novel class of anticancer drugs that selectively target one type of E3 ubiquitin ligase, shown to be activated in human cancers. To this end, we have focused on SAG (Sensitive to Apoptosis Gene), also known as RBX2/ROC2, a RING component of SCF (Skp1-Cullin-F-box proteins) E3 ubiquitin ligases, required for its activity. Our strong published results and unpublished preliminary data, using mouse transgenic and knockout models and cell-based mechanistic studies, demonstrated that 1) SAG positively regulates angiogenesis: angiogenesis is enhanced by SAG transgenic expression in skin tumors, and inhibited by Sag knockout during embryonic development, in teratomas derived from ES cells, and in B16 melanoma tumorigenesis; 2) SAG E3 promotes the degradation of a) neurofibromin 1 (NF1) to activate the RAS/MAPK, b) IkB to activate NFkB, c) DEPTOR to activate mTOR, leading to enhanced proliferation and survival; 3) SAG inactivation by siRNA knockdown or by small molecule SAG E3 inhibitor MLN4924 selectively suppresses the growth of human squamous cell carcinoma (SCC) cells; 4) Sag KO inhibits keratinocyte differentiation, and finally 5) SAG is overexpressed in all three developmental stages of human skin SCC (namely, actinic keratosis, SCC in situ, and invasive SCC). However, whether Sag plays an essential role in skin carcinogenesis induced by viral (HPV16 to inactivate p53 and RB), chemical (DMBA-TPA to activate Ras-AP1), or physical (UV) carcinogens, thus serving as a valid target for anti-skin cancer therapy, has not been systematically examined. The objectives of this application are to use tissue specific Sag knockout mouse models under physiological settings to investigate mechanistically the role of Sag in skin carcinogenesis triggered by various carcinogens. The central hypothesis is that SAG promotes angiogenesis, proliferation and tumorigenesis via targeted degradation of tumor suppressive substrates such as NF1, IκB and DEPTOR, leading to activation of the RAS, NFκB and mTOR pathways, respectively. Inactivation of SAG by genetic deletion or pharmaceutical inhibitor MLN4924 would cause the accumulation of these substrates to inactivate the RAS, NFκB, mTOR pathways leading to suppression of skin carcinogenesis. Three specific aims are proposed to test our hypothesis by determining the effect of Sag deletion on 1) skin angiogenesis and carcinogenesis, induced by viral oncogenes; 2) skin carcinogenesis, induced by DMBA/TPA or UV; and 3) mechanisms of Sag action. IMPACT: Our work uses skin-specific KO mouse models that recapitulate the development of human skin SCC to elucidate mechanistically that SAG E3 ligase is essential for skin carcinogenesis, thus serving as an attractive drug target for skin cancer. Our work is highly innovative and of significant impact with translational value by providing proof-of-concept evidence for future development of MLN4924 as a novel class of anti-cancer agent for the prevention and treatment of skin cancer.
描述(由申请人提供):靶向癌症治疗依赖于对癌症靶标的彻底验证。我们的长期目标是发现一类新型抗癌药物,选择性地靶向一种类型的 E3 泛素连接酶,该酶已被证明在人类癌症中被激活。为此,我们重点关注 SAG(细胞凋亡敏感基因),也称为 RBX2/ROC2,它是 SCF(Skp1-Cullin-F-box 蛋白)E3 泛素连接酶的 RING 成分,是其活性所必需的。我们使用小鼠转基因和敲除模型以及基于细胞的机制研究,已发表的强有力的结果和未发表的初步数据表明,1)SAG正向调节血管生成:皮肤肿瘤中的SAG转基因表达增强血管生成,并在胚胎发育过程中、ES细胞衍生的畸胎瘤和B16黑色素瘤肿瘤发生中被Sag敲除抑制; 2) SAG E3 促进 a) 神经纤维蛋白 1 (NF1) 的降解,以激活 RAS/MAPK,b) IkB 以激活 NFkB,c) DEPTOR 以激活 mTOR,从而增强增殖和存活; 3) 通过siRNA敲低或小分子SAG E3抑制剂MLN4924使SAG失活,选择性抑制人鳞状细胞癌(SCC)细胞的生长; 4)Sag KO抑制角质形成细胞分化,最后5)SAG在人类皮肤SCC的所有三个发育阶段(即光化性角化病、原位SCC和侵袭性SCC)中过表达。然而,Sag是否在病毒(HPV16灭活p53和RB)、化学(DMBA-TPA激活Ras-AP1)或物理(UV)致癌物诱导的皮肤癌发生中发挥重要作用,从而作为抗皮肤癌治疗的有效靶点,尚未得到系统研究。本申请的目的是在生理环境下使用组织特异性 Sag 敲除小鼠模型,从机制上研究 Sag 在各种致癌物引发的皮肤癌发生中的作用。核心假设是,SAG 通过靶向降解肿瘤抑制底物(如 NF1、IκB 和 DEPTOR)来促进血管生成、增殖和肿瘤发生,从而分别导致 RAS、NFκB 和 mTOR 通路的激活。通过基因缺失或药物抑制剂 MLN4924 灭活 SAG 会导致这些底物的积累,从而灭活 RAS、NFκB、mTOR 通路,从而抑制皮肤癌的发生。提出了三个具体目标,通过确定 Sag 缺失对 1)由病毒癌基因诱导的皮肤血管生成和癌发生的影响来检验我们的假设; 2)DMBA/TPA或紫外线诱发的皮肤癌; 3) 下垂作用机制。影响:我们的工作使用皮肤特异性 KO 小鼠模型来概括人类皮肤 SCC 的发展,从机制上阐明 SAGE E3 连接酶对于皮肤癌发生至关重要,从而作为皮肤癌的一个有吸引力的药物靶点。我们的工作具有高度创新性,具有重大转化价值,为 MLN4924 作为预防和治疗皮肤癌的新型抗癌药物的未来开发提供了概念验证证据。
项目成果
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{{ truncateString('YI SUN', 18)}}的其他基金
Role of SAG/RBX2 E3 Ubiquitin Ligase in Skin Carcinogenesis
SAG/RBX2 E3 泛素连接酶在皮肤癌发生中的作用
- 批准号:
8602514 - 财政年份:2013
- 资助金额:
$ 32.27万 - 项目类别:
Role of SAG/RBX2 E3 Ubiquitin Ligase in Skin Carcinogenesis
SAG/RBX2 E3 泛素连接酶在皮肤癌发生中的作用
- 批准号:
8451029 - 财政年份:2013
- 资助金额:
$ 32.27万 - 项目类别:
Anti-pancreatic tumorigenesis by inactivation of SAG/RBX2 E3 ubiquitin ligase
通过灭活 SAG/RBX2 E3 泛素连接酶来抗胰腺肿瘤发生
- 批准号:
8601690 - 财政年份:2013
- 资助金额:
$ 32.27万 - 项目类别:
Anti-pancreatic tumorigenesis by inactivation of SAG/RBX2 E3 ubiquitin ligase
通过灭活 SAG/RBX2 E3 泛素连接酶来抗胰腺肿瘤发生
- 批准号:
8450970 - 财政年份:2013
- 资助金额:
$ 32.27万 - 项目类别:
SAG E3 ubiquitin ligase in regulation of transformation and carcinogenesis
SAG E3 泛素连接酶在转化和癌变调控中的作用
- 批准号:
8478051 - 财政年份:2011
- 资助金额:
$ 32.27万 - 项目类别:
SAG E3 ubiquitin ligase in regulation of transformation and carcinogenesis
SAG E3 泛素连接酶在转化和癌变调控中的作用
- 批准号:
8677741 - 财政年份:2011
- 资助金额:
$ 32.27万 - 项目类别:
Mechanistic validation of SCF E3 ligase as a cancer and radiosensitizing target
SCF E3 连接酶作为癌症和放射增敏靶点的机制验证
- 批准号:
8625717 - 财政年份:2011
- 资助金额:
$ 32.27万 - 项目类别:
Mechanistic validation of SCF E3 ligase as a cancer and radiosensitizing target
SCF E3 连接酶作为癌症和放射增敏靶点的机制验证
- 批准号:
8447574 - 财政年份:2011
- 资助金额:
$ 32.27万 - 项目类别:
SAG E3 ubiquitin ligase in regulation of transformation and carcinogenesis
SAG E3 泛素连接酶在转化和癌变调控中的作用
- 批准号:
8842935 - 财政年份:2011
- 资助金额:
$ 32.27万 - 项目类别:
Mechanistic validation of SCF E3 ligase as a cancer and radiosensitizing target
SCF E3 连接酶作为癌症和放射增敏靶点的机制验证
- 批准号:
8054560 - 财政年份:2011
- 资助金额:
$ 32.27万 - 项目类别:
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