Elimination of Carcinogen-Induced Tumor Stem Cells by ATF5 Loss of Function.

通过 ATF5 功能丧失消除致癌物诱导的肿瘤干细胞。

• 批准号: 7531068
• 负责人: James M Angelastro
• 金额: $ 17.1万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7531068
• 关键词: Adult; Apoptosis; Apoptotic; Aspartate-Ammonia Ligase; Astrocytes; Binding; Biological Models; Brain; Brain Neoplasms; Brain Stem Neoplasms; Carcinogens; Cause of Death; Cell Cycle; Cell Death; Cell division; Cell model; Cells; Cessation of life; Characteristics; DNA; DNA Adducts; Dominant-Negative Mutation; Down-Regulation; Environmental Carcinogens; Ethylnitrosourea; Frequencies; Future; Generations; Genes; Genetic; Glial Differentiation; Glioblastoma; Glioma; Goals; Growth Factor; Heat Shock Protein 27; Human; In Vitro; Laboratories; Lead; Lesion; Localized; Malignant Glioma; Malignant neoplasm of brain; Mus; Mutation; Neoplasms; Neuraxis; Neuroepithelial, Perineurial, and Schwann Cell Neoplasm; Neuroglia; Neurons; Normal Cell; Nutritional Requirements; Pathway interactions; Patients; Play; Prohibit; Proliferating; Protein Overexpression; Proto-Oncogene Proteins c-sis; Public Health; Research; Role; Screening procedure; Small Interfering RNA; Specimen; Stem cells; Therapeutic Intervention; Transgenes; Tumor Promotion; Tumor Stem Cells; Undifferentiated; Work; activating transcription factor; cancer stem cell; cancer therapy; demographics; follow-up; functional loss; gain of function; in vivo; insight; loss of function; mouse model; neoplastic; neoplastic cell; nerve stem cell; postnatal; prenatal; prevent; progenitor; programs; pup; relating to nervous system; research study; stem; success; transcription factor; tumor; tumor growth; tumorigenesis

DESCRIPTION (provided by applicant): Activating transcription factor 5 (ATF5) is highly expressed in neural stem/progenitor cells, and disappears when these cells differentiate into neurons and astrocytes. Over expression of exogenous ATF5 maintains neural stem/progenitor cells in their undifferentiated state. By contrast, loss of functional ATF5, achieved through overexpression of its dominant negative or loss of ATF5 expression by small interfering RNA, accelerates neuronal and glial differentiation. High expression of ATF5 occurs in glioblastoma tumors. Expression of dominant negative ATF5 promotes apoptosis in neural tumors, but not in non-neoplastic cells both in vitro and in vivo. Long-term objectives are to determine whether brain neoplasm, arising from environmental carcinogens, promotes transformations of neural stem cells to tumor stem cells that in turn support the growth of tumors. We propose: (1) To create brain tumors in mouse models that resemble mutations of a growth factor amplified pathway and DNA- adduct genetic lesions. (2) Show that neural stem/progenitors constitutively overexpress endogenous ATF5 resulting from neoplastic conversion. 3) Blockage of ATF5 function prevents neoplasm, and leads to cell death of pre- existing neural tumor cells and their tumor stem cells, but spares non-neoplastic cells within the same brain. (4) Finally, we will substantiate previous work to show that blocked ATF5 promotes cell cycle exit in non-neoplastic stem/ progenitor cells, but neoplasm conversion globally leads to apoptosis through prohibited cell cycle exit and/or restriction in nutrient requirements. We hope these pioneer experiments will provide future insight for therapeutic intervention aimed at targeting ATF5 to treat brain tumors in patients. PUBLIC HEALTH RELEVANCE: Despite the continuing success in treatment of cancer, there has been only limited advancement in curing neural tumors such as malignant gliomas. Recent research in our laboratory has gained insight on the mechanism by which proliferating neural stem/progenitor cells become mature neurons and glia. One of the ways is through transcription factors that bind to DNA and turn on or off genes. We found that one such transcription factor, designated ATF5, turns off genes that would lead a proliferating stem/progenitor cell to turn into either a neuron or glia. Our hypothesis is that ATF5 is permanently turned on in brain stem tumor cells and that these cells are instructed to continue to divide, and are unable to change into mature non-dividing neurons or glial cells. We found that by interfering with the function of ATF5 or by removing it from proliferating neural progenitor cells, the latter cease or slow down cell division, and are able to turn into normal neurons and glia. In a glioblastoma brain tumor cell model system, we found that interference with ATF5 function causes death of the tumor cells. Thus, ATF5 may be a potential target for therapeutic intervention and a possible treatment for brain cancer.

描述（申请人提供）：激活转录因子5（ATF5）在神经干/祖细胞中高度表达，并在这些细胞分化为神经元和星形胶质细胞时消失。外源 ATF5 的过度表达可维持神经干/祖细胞处于未分化状态。相比之下，通过其显性失活的过度表达或小干扰RNA导致的ATF5表达丧失而导致功能性ATF5的丧失，会加速神经元和神经胶质细胞的分化。 ATF5 在胶质母细胞瘤中高表达。在体外和体内，显性失活 ATF5 的表达促进神经肿瘤细胞凋亡，但不促进非肿瘤细胞凋亡。长期目标是确定由环境致癌物引起的脑肿瘤是否促进神经干细胞向肿瘤干细胞的转化，从而支持肿瘤的生长。我们建议：(1) 在小鼠模型中创建类似于生长因子放大途径突变和 DNA 加合物遗传损伤的脑肿瘤。 (2)表明神经干/祖细胞组成性过度表达由肿瘤转化引起的内源性ATF5。 3) 阻断 ATF5 功能可防止肿瘤形成，并导致先前存在的神经肿瘤细胞及其肿瘤干细胞死亡，但不会影响同一大脑内的非肿瘤细胞。 (4)最后，我们将证实之前的工作，表明阻断 ATF5 促进非肿瘤干/祖细胞的细胞周期退出，但肿瘤转化通过禁止细胞周期退出和/或限制营养需求而全局导致细胞凋亡。我们希望这些开创性的实验将为未来针对 ATF5 治疗患者脑肿瘤的治疗干预提供见解。公共健康相关性：尽管在癌症治疗方面不断取得成功，但在治疗恶性神经胶质瘤等神经肿瘤方面进展有限。我们实验室最近的研究深入了解了增殖的神经干/祖细胞变成成熟神经元和神经胶质细胞的机制。其中一种方法是通过与 DNA 结合并打开或关闭基因的转录因子。我们发现这样一种转录因子，称为 ATF5，可以关闭导致增殖的干细胞/祖细胞转变为神经元或神经胶质细胞的基因。我们的假设是，ATF5 在脑干肿瘤细胞中永久开启，并且这些细胞被指示继续分裂，并且无法转变为成熟的非分裂神经元或神经胶质细胞。我们发现，通过干扰 ATF5 的功能或将其从增殖的神经祖细胞中去除，后者会停止或减慢细胞分裂，并能够转变成正常的神经元和神经胶质细胞。在胶质母细胞瘤脑肿瘤细胞模型系统中，我们发现干扰 ATF5 功能会导致肿瘤细胞死亡。因此，ATF5可能是治疗干预的潜在靶点以及脑癌的可能治疗方法。