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:
    8451029
  • 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 2017-12-31
  • 项目状态:
    已结题

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 Our strong published results and unpublished preliminary data, using mouse transgenic and knockout models and cell-based mechanistic studies, demonstrated that 1) SAG positively regulates angiogenesis: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, I?B and DEPTOR, leading to activation of the RAS, NF?B 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, NF?B, 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点的彻底验证。我们的长期目标是发现一类新的抗癌药物,选择性地靶向一种E3泛素连接酶,该酶在人类癌症中被激活。为此,我们专注于SAG(对凋亡敏感的基因),也称为RBX 2/ROC 2,SCF(Skp 1-Cullin-F-box蛋白)E3泛素连接酶的RING组分,其活性所需。我们利用小鼠转基因和敲除模型以及基于细胞的机制研究,强有力的已发表结果和未发表的初步数据表明:1)SAG正调控血管生成:在皮肤肿瘤中,SAG转基因表达增强血管生成,而在胚胎发育、ES细胞来源的畸胎瘤和B16黑色素瘤中,Sag敲除抑制血管生成; 2)SAG E3促进a)神经纤维蛋白1(NF 1)的降解以激活RAS/MAPK,B促进b)Ik B的降解以激活NF k B,c)DEPTOR的降解以激活mTOR,导致增强的增殖和存活; 3)通过siRNA敲低或通过小分子SAG E3抑制剂MLN 4924的SAG失活选择性地抑制人鳞状细胞癌(SCC)的生长细胞; 4)Sag KO抑制角质形成细胞分化,最后5)SAG在人皮肤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是否在由病毒(HPV 16至Rasp 53和RB)、化学(DMBA-TPA以激活Ras-AP 1)或物理(UV)致癌物诱导的皮肤致癌作用中起重要作用,从而作为抗皮肤癌治疗的有效靶点,尚未系统地研究。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,以机械地研究Sag在由各种致癌物引发的皮肤致癌作用中的作用。中心假设是,SAG促进血管生成,增殖和肿瘤发生,通过有针对性地降解肿瘤抑制底物,如NF 1,I?B和DEPTOR,导致RAS、NF?B和mTOR通路。通过基因缺失或药物抑制剂MLN 4924灭活SAG将导致这些底物的蓄积,从而破坏RAS、NF?B,导致抑制皮肤癌发生的mTOR途径。提出了三个具体的目标,以测试我们的假设,通过确定的影响,Sag删除1)皮肤血管生成和致癌作用,由病毒致癌基因诱导; 2)皮肤致癌作用,由DMBA/TPA或UV诱导;和3)的机制Sag的行动。影响:我们的工作使用皮肤特异性KO小鼠模型,其概括了人类皮肤SCC的发展,以从机理上阐明SAG E3连接酶对皮肤癌发生至关重要,从而作为皮肤癌的有吸引力的药物靶标。我们的工作具有高度创新性,通过为MLN 4924作为预防和治疗皮肤癌的新型抗癌药物的未来开发提供概念验证证据,具有重大的转化价值。

项目成果

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YI SUN其他文献

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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:
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:
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:
    8785658
  • 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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