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

点击翻译按钮获取中文摘要

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.