The Role of AP-1 and Other Transcription Factors in Cancer Cause and Prevention

AP-1 和其他转录因子在癌症病因和预防中的作用

• 批准号: 8552640
• 负责人: NANCY H. COLBURN
• 金额: $ 53.71万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8552640
• 关键词: Automobile Driving; Award; Biological Assay; Biological Factors; Biology; CCR; Cancer Etiology; Cancer Model; Cell Proliferation; Cell Survival; Cells; Chemicals; Chromatin; Collaborations; Coupled; DNA Binding; Development; Diagnostic Neoplasm Staging; Dominant-Negative Mutation; ERBB2 gene; Enzymes; Event; Exposure to; Family; Gene Expression Regulation; Gene Targeting; Genes; Genetic Transcription; HMGA1 gene; Human; Human Papillomavirus; I Kappa B-Alpha; Laboratories; Malignant Neoplasms; Malignant neoplasm of ovary; Mammary Neoplasms; Mammary Tumorigenesis; Medicine; Microarray Analysis; Modeling; Molecular Target; Mus; Neoplastic Cell Transformation; Oncogenes; Oxidation-Reduction; PTGS2 gene; Pathway interactions; Phosphorylation; Protein Binding; Protein Kinase C; Proteins; Research; Resistance; Role; STAT3 gene; Screening procedure; Signal Transduction; Skin Neoplasms; Specificity; Squamous cell carcinoma; Tetracyclines; Transcription Factor AP-1; Transgenic Mice; Tumor Cell Invasion; Tumor Promotion; Tumor stage; Ubiquitination; Ultraviolet B Radiation; Urokinase; analog; attenuation; cancer prevention; cancer site; carcinogenesis; drug discovery; efficacy testing; high throughput screening; inhibitor/antagonist; innovation; keratinocyte; lung carcinogenesis; mammary epithelium; mouse model; osteopontin; p65; prevent; promoter; response; small molecule; stromelysin 2; synaptotagmin I; transcription factor; trend; tumor progression; tumorigenesis

The AP-1 transcription factor is a heterodimer of Jun and Fos family proteins that binds to a specific sequence on the transcriptional promoter of certain genes and drives their transcription. Although basal AP-1 activity is needed for normal function, elevated AP-1 activity drives tumor progression in several human cancer sites. Keratinocyte-specific expression of Dominant Negative Jun in transgenic mice inhibits induced AP-1 and tumorigenesis without inhibiting cell proliferation or cell survival in multiple mouse models relevant to human carcinogenesis (Young et al., PNAS, 1999). Among these are mice whose skin tumor promotion response is elevated by expression of Human Papilloma Virus E7 (Young et al Molec Carc 2002) and mice induced to form squamous carcinomas by repeated exposure to UVB (Cooper et al Molec Cancer Res 2003). Tetracycline regulated expression of TAM 67 has been directed to mammary epithelia in collaboration with Powel Brown (Shen et al Dev Biol 2006) and has recently been tested for efficacy in preventing HER2/Neu induced mammary carcinogenesis. The results show substantial inhibition by the AP-1 blocker of preneoplastic as well as early and later stage tumor development (Shen et al Ca Prev Res 2008). Importantly, TAM67 expression was silenced in mammary tumors that developed. Inducible TAM67 has been found also to inhibit chemically induced lung carcinogenesis in collaboration with the laboratory of Jay Tichelaar (Cancer Prev Research 2010). The transcription factor NFkappa B is coordinately regulated with AP-1, suggesting the possible importance of both factors in transformation (Li et, Cancer Res 1997). Recent observations have identified NFkB non-responsiveness as an explanation for transformation non-responsiveness in the JB6 model (Hsu et al, Cancer Res 2001, Hu et al Carcinogenesis 2004). Transformation resistant cells owe their nonresponsiveness to an inability to activate NFkappa B p65 protein. p65 phosphorylation at S536 is important for DNA binding and for ubiquitination and degradation of inhibitor IkappaB alpha (Hu et al Molec Carcinog 2005). The observation that targeting AP-1 and NFkB elevation prevents tumor promotion and progression has been extended from the mouse JB6 model to mouse and human keratinocyte progression models, and to transgenic mouse models. Transgenic mice expressing AP-1/ NFkB inhibitor TAM 67 present a valuable opportunity to identify AP-1 or NFkB target genes whose expression is critical to neoplastic transformation. Expression microarray analysis has revealed TAM67 target genes that are being queried for functional significance in driving carcinogenesis. Such target genes may be promising new molecular targets for cancer prevention (Young et al Trends in Molec Medicine 2003). Recent studies have established the importance of chromatin architectural protein HMGA1 (Dhar et al Oncogene 2004), COX-2, osteopontin, urokinase plasminogen activator, Cxcl1 and MMP-10 (Matthews et al Cancer Res 2007) as functionally significant TAM67 targets. One of the recently discovered TAM67/AP-1 target genes is sulfiredoxin, a redox enzyme that is functionally significant both in tumor promotion and invasion as well as elevated in human cancer (Wei Q, et al, PNAS 2008 and PNAS 2011). The most recently discovered target of the AP-1 blocker is Wnt5a which signals through a non-canonical pathway involving protein kinase C and STAT3 to drive oncogenesis in several models (Kang et al Genes and Cancer, 2012 in press. A drug discovery project in collaboration with the Molecular Targets Laboratory has identified compounds that mimic the specificity of TAM67, i.e. that inhibit AP-1 and/or NFkB and prevent carcinogenesis without inhibiting cell proliferation or cell survival. The primary AP-1 high throughput screen of 300,000 synthetic and natural products coupled to a cell proliferation (XTT) assay yielded a small set of AP-1 hits(Ruocco et al J Biomolec Screening 2007). The secondary assay has assessed inhibition of NFkB and identified an AP-1 inhibitor that is even more active against NFkappa B (Kang et al Mol Ca Ther, 2009). The new Chemical Biology Laboratory, CCR is generating analogs of this NFkappaB inhibitor and collaborating with Cristina Annunziata (MOB, CCR), winner of a Directors Innovation Award to assess its possible effectivenss against human ovarian cancer. In summary, recent accomplishments for this Project include 1) the discovery of new AP-1 regulated genes whose attenuation is responsible for the carcingenesis suppressing activity of AP-1 blocker TAM67, notably Sulfiredoxin and Wnt5a, and 2) the discovery of new small molecules that target AP-1 or NFkappaB without inhibiting cell viability.

AP-1转录因子是JUN和FOS家族蛋白的异二聚体，与某些基因的转录启动子上的特定序列结合并驱动其转录。尽管正常功能需要基础AP-1活性，但升高的AP-1活性驱动了几个人类癌症部位的肿瘤进展。在转基因小鼠中显性阴性JUN的角质形成细胞特异性表达抑制诱导的AP-1和肿瘤发生，而无需抑制与人类致癌的多种小鼠模型中细胞增殖或细胞存活（Young等，PNAS，1999）。 其中包括小鼠的小鼠通过人类乳头瘤病毒E7的表达升高皮肤肿瘤的促进反应（Young等人Carc 2002）和通过反复暴露于UVB（Cooper等人的MOLEC CANCER CANCE RES RES 2003）而诱导形成鳞状癌的小鼠。 四环素调节TAM 67的表达已与Powel Brown合作（Shen等人Dev Biol 2006）指向乳腺上皮，并最近对防止HER2/NEU诱导的乳腺癌发生的功效进行了测试。结果表明，肿瘤肿瘤的AP-1阻滞剂以及早期肿瘤的发展得到了重大抑制（Shen等CA Prev Res 2008）。重要的是，在发展的乳腺肿瘤中沉默了TAM67。还发现诱导型TAM67与Jay Tichelaar实验室合作抑制化学诱导的肺癌发生（Cancer Prev Research 2010）。转录因子NFKAPPA B与AP-1协调调节，这表明这两个因素在转化中的可能性可能很重要（Li et，Cancer Res 1997）。最近的观察结果已经确定了NFKB无反应性是JB6模型中转化无反应性的解释（Hsu等，Cancer Res 2001； Hu等人Carcinogenogeny 2004）。抗转化的细胞不反应性，无法激活NFKAPPA B p65蛋白。 S536处的p65磷酸化对于DNA结合以及抑制剂ikappab alpha的泛素化和降解至关重要（Hu等人Molec Carcinog 2005）。靶向AP-1和NFKB升高可以阻止肿瘤促进和进展的观察结果已从小鼠JB6模型扩展到小鼠和人角质形成细胞的进程模型以及转基因小鼠模型。表达AP-1/ NFKB抑制剂TAM 67的转基因小鼠提供了一个宝贵的机会，可以识别AP-1或NFKB靶基因，其表达对肿瘤转化至关重要。 表达微阵列分析显示，TAM67靶基因在驱动致癌作用中的功能显着性。这种靶基因可能是预防癌症的新分子靶标（Molec Medicine 2003中的Young等人趋势）。最近的研究确定了染色质结构蛋白HMGA1（Dhar等人Oncogene 2004），COX-2，骨桥蛋白，尿激酶纤溶酶原激活剂，CXCL1和MMP-10（Matthews等人Cancer Res 2007）是功能上有效的TAM67目标。 最近发现的TAM67/AP-1靶基因之一是磺氧还原蛋白，这是一种氧化还原酶，在肿瘤促进和侵袭中在功能上具有重要意义，并且在人类癌症中升高（Wei Q等，PNAS 2008和PNAS 2011）。 AP-1阻滞剂的最新发现的目标是Wnt5a，它通过涉及蛋白激酶C和Stat3的非规范途径发出信号，以驱动多种模型（Kang et al Genes and Cancer，2012年，在新闻中。与分子目标合作的药物发现项目，与分子目标合作的药物发现项目都可以模拟于temi and ap-ap-ap-ap-ap-ap-1.无抑制细胞增殖或细胞存活的致癌作用。 （Kang等人CA，2009年）。 总而言之，该项目的最新成就包括1）发现新的AP-1调节基因，其衰减负责抑制AP-1阻滞剂TAM67（尤其是Sulfiredoxin and Wnt5a）的碳碳纤维抑制活性，以及​​2）发现靶向AP-1或NFKABAB的新小型分子而无需抑制Cell Vaivia的新小分子。