Role of Lipocalin 24p3 in Apoptosis and Leukemia

脂质运载蛋白 24p3 在细胞凋亡和白血病中的作用

• 批准号: 7221162
• 负责人: MICHAEL R GREEN
• 金额: $ 25.21万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-12 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7221162
• 关键词: Animal Model; Apoptosis; Apoptotic; Cell Death; Cell Line; Cell Surface Receptors; Cell Survival; Cells; Chelating Agents; Chronic Myeloid Leukemia; Disease; Gene Activation; Genes; Genetic Transcription; Glucocorticoids; Goals; Growth Factor; Helper-Inducer T-Lymphocyte; Imatinib; Induction of Apoptosis; Interleukin-3; Iron; Knockout Mice; Laboratories; Leucine Zippers; Lymphoid Cell; Malignant lymphoid neoplasm; Mediating; Modeling; Molecular; Molecular Profiling; Mus; Myeloproliferative disease; Pathway interactions; Patients; Physiological; Physiology; Play; Proteins; RNA Interference; Resistance; Role; Sampling; Transcriptional Activation; autocrine; base; bcr-abl Fusion Proteins; cancer cell; cancer therapy; cell transformation; chemotherapeutic agent; cytokine; deprivation; killings; leukemia; novel; paracrine; programs; research study; transcription factor

DESCRIPTION (provided by applicant): Programmed cell death, apoptosis, is a critical aspect of normal physiology as well as the genesis and treatment of cancer. Certain apoptotic pathways are transcriptionally regulated; in these cases, apoptosis is induced by the transcriptional activation of genes encoding proapoptotic proteins. This application focuses on the 24p3/24p3R transcriptionally-regulated proapoptotic pathway that our laboratory discovered and has been studying for the past several years. We originally identified 24p3 as the gene undergoing maximum transcriptional stimulation following induction of apoptosis by cytokine-deprivation of interleukin 3 (IL-3) dependent cells. 24p3 is a secreted lipocalin, which we have found induces apoptosis when added to a variety of lymphoid cells. These and other results revealed a model in which IL-3 deprivation activates 24p3 transcription, leading to synthesis and secretion of 24p3, which induces apoptosis through an autocrine/paracrine pathway. We have isolated the 24p3 cell surface receptor (24p3R) and found that 24p3 induces apoptosis through a novel pathway culminating in a decrease in intracellular iron levels. The decrease in intracellular iron induces expression of the proapoptotic protein Bim, resulting in apoptosis. Intracellular iron delivery blocks induction of Bim and suppresses apoptosis due to 24p3 addition or IL-3 deprivation. In this application we propose experiments to study the role of the 24p3/24p3R proapoptotic pathway in normal physiology and myeloproliferative disease using cell lines, patient samples and animal models. The basis by which decreased intracellular iron induces apoptosis is not well understood. We will continue to characterize the apoptotic pathway induced by 24p3 and by iron chelators. Expression profiling and RNA interference will be used to identify transcriptionally activated genes involved in 24p3- and iron chelator-mediated apoptosis. Our preliminary results suggest a possible role for the 24p3/24p3R pathway in glucocorticoid-mediated apoptosis and glucocorticoid-resistance, which we will continue to investigate. We have found that the BCR-ABL oncoprotein counteracts the 24p3/24p3R proapoptotic pathway by misregulating expression of 24p3 and 24p3R. These results reveal a new and unanticipated aspect of the mechanism by which BCR-ABL promotes cell survival. We will continue to analyze the generality of this result and study the basis by which 24p3 and 24p3R transcription is misregulated. We have derived 24p3 homozygous knockout mice, which will be used to study the contribution of the 24p3/24p3R proapoptotic pathway to BCR/ABL-induced myeloproliferative disease.

描述（由申请人提供）：程序性细胞死亡，细胞凋亡，是正常生理学以及癌症发生和治疗的关键方面。某些凋亡途径是转录调控的;在这些情况下，凋亡是由编码促凋亡蛋白的基因的转录激活诱导的。本申请的重点是我们实验室发现的24 p3/24 p3 R转录调节的促凋亡途径，并在过去几年中一直在研究。我们最初确定24 p3作为基因经历最大的转录刺激诱导凋亡后，由白细胞介素3（IL-3）依赖细胞的白细胞介素剥夺。24 p3是一种分泌型脂质运载蛋白，我们发现当将其加入到各种淋巴细胞中时，它会诱导细胞凋亡。这些和其他结果揭示了一种模型，其中IL-3剥夺激活24 p3转录，导致24 p3的合成和分泌，其通过自分泌/旁分泌途径诱导细胞凋亡。我们已经分离了24 p3细胞表面受体（24 p3 R），并发现24 p3通过一种新的途径诱导细胞凋亡，最终导致细胞内铁水平下降。细胞内铁的减少诱导促凋亡蛋白Bim的表达，导致细胞凋亡。细胞内铁传递阻断Bim的诱导并抑制由于24 p3添加或IL-3剥夺引起的细胞凋亡。在本申请中，我们提出了使用细胞系、患者样本和动物模型来研究24 p3/24 p3 R促凋亡途径在正常生理学和骨髓增生性疾病中的作用的实验。细胞内铁减少诱导细胞凋亡的基础尚不清楚。我们将继续表征24 p3和铁螯合剂诱导的凋亡途径。表达谱分析和RNA干扰将用于识别参与24 p3和铁螯合剂介导的细胞凋亡的转录激活基因。我们的初步结果表明，24 p3/24 p3 R途径在糖皮质激素介导的细胞凋亡和糖皮质激素抵抗中可能发挥作用，我们将继续研究。我们发现BCR-ABL癌蛋白通过错误调节24 p3和24 p3 R的表达来抵消24 p3/24 p3 R促凋亡通路。这些结果揭示了BCR-ABL促进细胞存活的机制的一个新的和未预料到的方面。我们将继续分析这一结果的普遍性，并研究24 p3和24 p3 R转录失调的基础。我们已经获得了24 p3纯合子敲除小鼠，这将用于研究24 p3/24 p3 R促凋亡通路的BCR/ABL诱导的骨髓增生性疾病的贡献。