NOVEL GENE REARRANGED WITH THE RAR ALPHA LOCUS

描述：（改编自研究者摘要） 白血病锌指蛋白（PLZF）是一种转录因子， 在造血祖细胞中表达，与视黄酸融合， t（11;17）相关急性早幼粒细胞白血病中酸性受体-a（RAR α）的研究 （APL）。 t（11;17）APL是一种独特的综合征，与其他类型的APL不同， 常见的t（15;17）APL对维甲酸或化疗无反应。 t（11;17）APL中产生的PLZF-RAR α是一种异常的维甲酸 与t（15;17）的PML-RAR α融合体相似的受体为显性阴性 野生型RAR α的抑制剂。 因此，白血病发生的一个共同机制是 破坏视黄酸信号传导。 RAR α与PLZF的融合可以 选择一个积极的临床表型，由于破坏的 PLZF在正常骨髓发育中重要作用。 PLZF是一个 序列特异性DNA结合转录抑制因子和生长抑制因子 抑制剂诱导骨髓细胞中的G1/S停滞和程序性细胞死亡。 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 与肿瘤形成、发育和分化有关。 POZ域 PLZF蛋白的二聚化和抑制基因表达可能是必需的 转录和PLZF的转录和生物学效应， PLZF-RAR α嵌合体。 药物的作用方式及分子靶蛋白 POZ域未知。 该研究将：1。 PLZF如何控制骨髓细胞的确定 通过阐明PLZF靶基因的生长和分化， PLZF蛋白在体外和体内如IL-6、细胞周期蛋白A和其它待 通过全基因组PCR鉴定。 2. 定义一个进化上保守的 蛋白基序，POZ结构域，在转录调节中起作用， 通过保守残基的诱变和配偶体的鉴定 蛋白质使用酵母双杂交系统。 3. 定义蛋白质蛋白质 在正常骨髓生成中发挥作用的相互作用网络， 白血病发生（PML-PLZF，N-Cor-PLZF）。 4. 扩展基因知识 通过顺式作用的表征在早期造血中的调节 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.