Regulation of Nanog in DNA damage response, development and tumorigenesis

Nanog 在 DNA 损伤反应、发育和肿瘤发生中的调节

• 批准号: 7494644
• 负责人: YANG XU
• 金额: $ 26.48万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-10 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7494644
• 关键词: Adult; Binding; Breast Carcinoma; Breeding; Cell Differentiation process; Cell Lineage; Cell Proliferation; Cells; Chromatin Structure; Co-Immunoprecipitations; Complementary DNA; DNA Damage; DNA strand break; Data; Development; Dominant-Negative Mutation; Down-Regulation; Eating; Embryo; Epithelial Cells; Failure; Family member; Future; Genetic; Genetic Transcription; Germ cell tumor; Health; Homeodomain Proteins; Human; Hypoxanthine; Hypoxanthines; In Vitro; Knock-in Mouse; Light; Malignant Neoplasms; Mammary Neoplasms; Mammary Tumorigenesis; Mammary gland; Mediating; Mus; Mutation; Pathway interactions; Physiological; Poly(ADP-ribose) Polymerases; Process; Protein Overexpression; Protein p53; Proteins; Proteomics; Rate; Recruitment Activity; Regulation; Replacement Therapy; Research Personnel; Resistance; Role; Somatic Cell; Staging; Stem cells; Stimulus; TP53 gene; Testing; Tissues; Transgenic Mice; Tretinoin; Yang Deficiency; base; blastocyst; cell type; embryonic stem cell; human embryonic stem cell; in vivo; malignant breast neoplasm; pluripotency; prevent; promoter; protein protein interaction; research study; response; self-renewal; stem; transcription factor; tumor; tumorigenesis

DESCRIPTION (provided by applicant): Embryonic stem cells (ESCs) are capable of unlimited self-renewal and retain the pluripotency to differentiate into all cell lineages in the body. Since ESCs undergo robust cellular proliferation and DNA damage occurs during normal cellular proliferation, it is critical for ESCs to possess stringent mechanisms to maintain genetic stability to prevent the passage of DNA damage to the progeny. Consistent with this notion, the spontaneous mutation rate is much lower in ESCs than in somatic cells. The mechanism to maintain genetic stability in ESCs remains unclear. I hypothesize that one primary mechanism to rid of DNA damaged-ESCs is to induce their differentiation into other cell types in order to maintain the genetic integrity of the self-renewing pool of ESCs. Recent discovery of the homeodomain protein Nanog as the master regulator of self-renewal allows us test this hypothesis. We hypothesized that the expression and activities of Nanog might be suppressed in response to DNA damage. In support of this notion, our recent findings indicate that DNA damage induces the differentiation of ESCs by suppressing the Nanog expression. Tumor suppressor p53 is required for this process and suppresses the expression of Nanog by direct binding to its promoter. I propose three aims to further elucidate the regulation of the expression and activity of Nanog after DNA damage and during ESC differentiation, and to study the potential roles of Nanog in cancers. Aim 1. To elucidate physiological importance of p53 family members-dependent downregulation of Nanog in mouse and human ESCs. Aim 2. Regulation of Nanog activities through protein-protein interaction in ESCs after DNA damage. Aim 3. To study the roles of Nanog in development, genetic stability and tumorigenesis. These studies have direct relevance to human health. In this context, the studies of the potential role of Nanog in tumorigenesis will help to develop new therapy for Nanog-overexpressing cancers, including germ cell tumors and breast carcinomas. In addition, these studies will shed light on mechanism that maintains genetic stability in human ESCs, which have a great potential for future human cell/tissue replacement therapy.

描述（由申请人提供）：胚胎干细胞（ESC）能够无限制的自我更新并保留多能分化到体内所有细胞谱系中的多能。由于ESC在正常的细胞增殖过程中发生强大的细胞增殖和DNA损伤，因此ESC具有严格的机制以保持遗传稳定性以防止DNA损害对后代的损害至关重要。与这个概念一致，ESC的自发突变率比在体细胞中低得多。维持ESC遗传稳定性的机制尚不清楚。我假设摆脱DNA损坏的ESC的一种主要机制是诱导它们分化为其他细胞类型，以维持ESC的自我更新库的遗传完整性。最新发现同源域蛋白Nanog作为自我更新的主要调节剂使我们可以检验这一假设。我们假设纳米的表达和活性可能会响应DNA损伤而受到抑制。为了支持这一概念，我们最近的发现表明，DNA损伤通过抑制纳米表达来诱导ESC的分化。此过程需要抑制肿瘤p53，并通过直接结合其启动子来抑制Nanog的表达。我提出三个旨在进一步阐明DNA损伤和ESC分化过程中Nanog的表达和活性的调节，并研究Nanog在癌症中的潜在作用。目的1。阐明p53家庭成员依赖于小鼠和人类ESC中纳米的下调的生理重要性。 AIM 2。通过DNA损伤后ESC中蛋白质蛋白质相互作用来调节Nanog活动。目的3。研究纳米在发育，遗传稳定性和肿瘤发生中的作用。这些研究与人类健康有直接的相关性。在这种情况下，对纳米在肿瘤发生中的潜在作用的研究将有助于开发用于过表达纳米的癌症的新疗法，包括生殖细胞肿瘤和乳腺癌。此外，这些研究将阐明维持人ESC遗传稳定性的机制，该机制具有未来人类细胞/组织替代疗法的巨大潜力。