GR Impairment in Carconogenesis: Tumor Suppressor Role

致癌作用中的 GR 损伤：肿瘤抑制作用

• 批准号: 7938161
• 负责人: THOMAS J SLAGA
• 金额: $ 16.94万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7938161
• 关键词: Adult; Affect; Animals; Carcinogens; Carcinoma; Cell Line; Cell physiology; DNA biosynthesis; Development; Diagnostic Neoplasm Staging; Epidermis; Genes; Glucocorticoid Receptor; Glucocorticoids; Goals; Growth; Hormones; Impairment; In Vitro; Inflammation; Inflammatory Response; Malignant Epithelial Cell; Mediating; Mus; Nuclear; Papilloma; Physiological; Play; Proliferating; Property; Repression; Resistance; Role; Skin; Skin Carcinogenesis; Skin Neoplasms; Skin Papilloma; Squamous Cell Papillomas; Squamous cell carcinoma; Staging; Tetanus Helper Peptide; Transgenic Animals; Transgenic Mice; Tumor Promoters; Tumor Suppressor Proteins; Tumor stage; Up-Regulation; carcinogenesis; glucocorticoid-induced orphan receptor; in vivo; inhibitor/antagonist; keratin 5; keratinocyte; overexpression; prevent; promoter; receptor function; skin hyperplasia; transcription factor; tumor; tumorigenesis; tumorigenic; ubiquitin ligase

DESCRIPTION (provided by applicant): Glucocorticoid hormones are very potent inhibitors of physiological DNA synthesis in keratinocytes in vivo. These hormones are also very effective in preventing carcinogen- and tumor promoter-induced skin hyperplasia, inflamination, and mouse skin tumor formation when applied to skin together with a carcinogen or a tumor promoter. We and others have shown, however, that glucocorticoids do not affect the growth of either established papillomas, squamous ceil carcinomas (SCC), or transformed keratinocytes in vitro. In addition, we recently found that glucocorticoids do net affect glucocorticoid-responsive genes in transformed keratinocytes both; in vitro/and in vivo. The glucocorticoid control of cellular functions is mediated by the glucocorticoid receptor (GR), a well-known transcription factor. We have found that NF-KB transcription factor is constitutively activated in mouse skin tumors which appears to alter some of GR functions. We have also found that this activation of NF-KB is primarily due to up-regulation of SCFmHOS ubiquitin ligase. We have generated skin-targeted transgenic mice over-expressing GR under the control of keratin 5 (K5) promoter. These adult transgenic mice have impaired proliferative and inflammatory responses to skin tumor promoters. Our initial studies showed that K5.GR transgenic animals are resistant to /-as-induced tumorigenesis. The constitutively nuclear overexpression and activation of GR in the epidermis dramatically inhibited skin tumor development in K5.GR/ras+ double transgenic mice in terms of number of animals that develop tumors, number of tumors per animal, and tumor size. We propose to prove the hypothesis that GR functions as a tumor suppressor in mouse skin carcinogenesis. Pursuant to this goal, the specific aims are: 1) To develop animals deficient in the expression of GR in skin, and analyze their sensitivity to skin carcinogenesis. 2) To determine whether transrepression activities of GR are sufficient to suppress tumorigenic properties of mouse skin papilloma and carcinoma cell lines. 3) To determine the stage(s) of carcinogenesis where GR plays a role of tumor suppressor a) develop transgenic animals with the conditional expression of GR in skin (TRE.GR X K5.Tet-On). b) analyze the sensitivity of these mice to skin carcinogenesis, when over-expression of GR induced at different stages of tumor development. 4) To analyze the effects of dissociated glucocorticoids on skin inflammation, keratinocyte proliferation, and on skin tumor development.

描述（由申请人提供）：糖皮质激素是体内角质形成细胞中生理DNA合成的非常有效的抑制剂。这些激素在预防致癌物和肿瘤诱导的皮肤增生，炎症和小鼠皮肤肿瘤形成时也非常有效，当时是与致癌物或肿瘤启动子一起施加到皮肤时。但是，我们和其他人表明，糖皮质激素不会影响已建立的乳头状瘤，鳞状Ceil癌（SCC）或体外转化的角质形成细胞的生长。此外，我们最近发现，糖皮质激素确实会影响转化的角质形成细胞中的糖皮质激素反应基因。体外/体内。细胞功能的糖皮质激素控制是​​由糖皮质激素受体（GR）介导的，这是一种众所周知的转录因子。我们发现，NF-KB转录因子在小鼠皮肤肿瘤中被组成性激活，这似乎改变了某些GR功能。我们还发现，NF-KB的激活主要是由于SCFMHOS泛素连接酶的上调。我们已经在角蛋白5（K5）启动子控制下产生了过表达GR的皮肤转基因小鼠。这些成年的转基因小鼠对皮肤肿瘤启动子的增生和炎症反应受损。我们的初步研究表明，K5.GR转基因动物对 / - AS诱导的肿瘤发生性具有抗性。表皮中GR的组成性核过表达和激活在K5.gr/RAS+双重转基因小鼠中显着抑制了皮肤肿瘤的发育，就发生肿瘤的动物数量，每只动物的肿瘤数量和肿瘤大小而言。我们建议证明GR在小鼠皮肤致癌作用中起肿瘤抑制的假设。根据这一目标，具体目的是：1）发展动物在皮肤中的GR表达不足，并分析其对皮肤致癌的敏感性。 2）确定GR的反抑制活性是否足以抑制小鼠皮肤乳头状瘤和癌细胞系的肿瘤性特性。 3）确定癌症发生的阶段，其中gr起抑制肿瘤的作用a）发展具有皮肤中GR条件表达的转基因动物（TRE.GR x K5.TET-on）。 b）分析这些小鼠对皮肤致癌的敏感性，当在肿瘤发育的不同阶段过度表达GR时。 4）分析解离的糖皮质激素对皮肤炎症，角质形成细胞增殖和皮肤肿瘤发育的影响。

项目成果

Dietary D-glucarate effects on the biomarkers of inflammation during early post-initiation stages of benzo[a]pyrene-induced lung tumorigenesis in A/J mice.

膳食 D-葡萄糖二酸对 A/J 小鼠苯并[a]芘诱导的肺肿瘤发生早期启动后阶段炎症生物标志物的影响。

• DOI: 10.3892/ol.2010.221
• 发表时间: 2011
• 期刊: Oncology letters
• 影响因子: 2.9
• 作者: Zoltaszek,Robert;Kowalczyk,Piotr;Kowalczyk,MagdalenaC;Hanausek,Margaret;Kilianska,ZofiaM;Slaga,ThomasJ;Walaszek,Zbigniew
• 通讯作者: Walaszek,Zbigniew

Disruption of eyelid and cornea development by targeted overexpression of the glucocorticoid receptor.

通过糖皮质激素受体的靶向过度表达来破坏眼睑和角膜发育。

• 发表时间: 2003
• 期刊: The International journal of developmental biology.
• 作者: Cascallana,JoseLuis;Bravo,Ana;Page,Angustias;Budunova,Irina;Slaga,ThomasJ;Jorcano,JoseL;Perez,Paloma
• 通讯作者: Perez,Paloma