NOVEL GENE REARRANGED WITH THE RAR ALPHA LOCUS

描述：(改编自研究人员的摘要)早幼粒细胞 白血病锌指蛋白(PLZF)是一种高度转录因子 在造血祖细胞中表达，与维甲酸融合 T(11；17)相关的急性早幼粒细胞白血病患者的酸性受体-a (APL)。T(11；17)APL是一种独特的综合征，不同于 常见的t(15；17)APL对维甲酸或化疗无反应。 在t(11；17)APL中产生的PLZF-RARA是一种异常的维甲酸 与t(15；17)的PML-RARA融合一样的受体为显性阴性 野生型RARA的抑制剂。因此，白血病发生的一个共同机制是 维甲酸信号的中断。RARA与PLZF的融合可能 选择具有侵袭性的临床表型，因为 PLZF在正常髓系发育中的重要作用。PLZF是一种 序列特异性DNA结合转录抑制子与生长 抑制子诱导髓系细胞G1/S停滞和程序性死亡。 PLZF蛋白包含一个进化上保守的基序，称为POZ (痘病毒锌指)结构域，在其他锌指蛋白中发现 与肿瘤的发生、发展和分化有关。POZ域 PLZF蛋白对基因二聚化和抑制似乎是必需的 转录以及PLZF和PLZF的转录和生物学效应 PLZF-RARA嵌合体。其作用方式及分子靶蛋白 POZ结构域未知。 拟议的研究将：1.确定PLZF是如何控制髓系细胞的 通过阐明PLZF结合的靶基因实现生长和分化 PLZF蛋白在体外和体内如IL-6、Cyclin A等待定 经全基因组聚合酶链式反应鉴定。2.定义一个进化上保守的 蛋白质基序，POZ结构域，在转录调控中发挥作用， 通过对保守残基的诱变和伴侣的鉴定 蛋白质使用酵母双杂交系统。3.定义蛋白质--蛋白质 相互作用网络在正常的骨髓生成和 白血病发生(PML-PLZF，N-COR-PLZF)。4.拓展基因知识 顺式作用在早期造血调控中的作用 控制PLZF表达的序列。

DESCRIPTION: (adapted from the investigator's abstract) The promyelocytic leukemia zinc finger (PLZF) protein is transcription factor, highly expressed in hematopoietic progenitor cells, that is fused to the retinoic acid receptor-a (RAR a) in t(11;17)-associated acute promyelocytic leukemia (APL). The t(11;17) APL is a distinct syndrome which, unlike the more common t(15;17) APL is unresponsive to retinoic acid or chemotherapy. PLZF-RARa which is generated in t(11;17) APL is an aberrant retinoid receptor which like the PML-RARa fusion of t(15;17) was a dominant negative inhibitor of wild-type RARa. Hence a common mechanism in leukemogenesis is disruption of retinoic acid signaling. The fusion of RARa to the PLZF may select for an aggressive clinical phenotype due to the disruption of the important function of PLZF in normal myeloid development. PLZF is a sequence specific DNA-binding transcriptional repressor and a growth suppressor inducing G1/S arrest and programmed cell death in myeloid cells. The PLZF protein contains an evolutionarily conserved motif called a POZ (poxvirus zinc finger) domain, found in other zinc finger proteins implicated in neoplasia, development and differentiation. The POZ domain appears to be necessary for PLZF protein to dimerize and repress gene transcription and for the transcriptional and biological effects of PLZF and the PLZF-RARa chimera. The mode of action and molecular target proteins of the POZ domains are unknown. The proposed research will: 1. Determine of how PLZF controls myeloid cell growth and differentiation by elucidation of PLZF target genes which bind the PLZF protein in vitro and in vivo such as IL-6, cyclin A and other to be identified by whole genome PCR. 2. Define how an evolutionarily conserved protein motif, the POZ domain, functions in transcriptional regulation, though mutagenesis of conserved residues and identification of partner proteins using the yeast two hybrid system. 3. Define protein-protein interaction networks that play a role in normal myelopoiesis and leukemogenesis (PML-PLZF, N-Cor-PLZF). 4. Extend knowledge of gene regulation in early hematopoiesis through characterization of the cis-acting sequences controlling expression of PLZF.