C-MYC PROTO-ONCOGENE TRANSCRIPTIONAL ELONGATION BLOCK

描述（改编自申请人的摘要）：c-myc原癌基因， 其表达与正常细胞的生长和分化有关， 在许多肿瘤状态中异常表达，包括淋巴瘤， 白血病和小细胞肺癌。 分子分析 正常和肿瘤细胞中c-myc基因表达的调节 已经发现了转录调控的新机制， 真核基因表达 c-myc表达的一个控制水平是 转录本的数量和比例的调节， 两个c-myc启动子，P1和P2。 第二种新的转录模式 控制，转录延伸的阻断，也在正常细胞中受到调节。 细胞 这种机制最初在人类c-myc基因中被描述， 基因和鼠c-myc基因，控制启动的量， 转录延伸超过外显子1的3'末端的阻断， 产生全长c-myc转录物。 c-myc延长阻滞 以启动子特异性和可调节方式。 转录 起始于P1启动子的组成型读段通过外显子1阻断， 而P2启动子的转录可以被调节为 通过或被封锁。 在正常细胞中，P2是主要的启动子。 相反，在伯基特淋巴瘤（BL）细胞中，其特征在于： 并置c-myc和免疫球蛋白（IG）序列易位， 是转录起始主要转移到P1启动子。 因此，BL细胞中的延伸阻断被废除，导致高表达。 水平和/或组成型合成的c-myc RNA。 研究者 工作假设是，因素赋予终止或抗终止 活性的RNA聚合酶II复合物在启动子特异性的方式。 这些因子修饰聚合酶复合体， 下行阻塞信号。 在正常细胞中，这种关联是可调节的 在P2启动子处，其中在P1启动子处形成的复合物赋予 结构通读。 在BL细胞中，向P1转录的转变可能 可能是由于存在抑制P2活性的反式作用因子 和/或增加P1利用，或由于对启动子的顺式效应 c-myc启动子的邻近性所施加的利用和强度， IG序列作为易位的结果。 这个目标 建议是确定启动子特异性元件和反式因子 在赋予聚合酶II通读和“阻断”模式中至关重要 复合物转录c-myc基因，并确定分子基础 c-myc延伸阻断和组成性表达的废除 BL.

DESCRIPTION (Adapted from applicant's abstract): The c-myc proto-oncogene, whose expression is linked to growth and differentiation in normal cells, is expressed aberrantly in many neoplastic states, including lymphomas, leukemias and small cell lung carcinomas. Molecular analyses of the regulation of expression of the c-myc gene in normal and neoplastic cells have uncovered novel mechanisms for the transcriptional regulation of eukaryotic gene expression. One level of control of c-myc expression is modulation in the quantity and ratio of transcripts that initiate from the two c-myc promoters, P1 and P2. A second and novel mode of transcriptional control, a block to transcription elongation, is also regulated in normal cells. This mechanism, which was described originally in the human c-myc gene and in the murine c-myc gene, controls the amount of initiated transcription that elongates past a block at the 3' end of exon 1 to produce full length c-myc transcripts. The c-myc elongation block operates in both a promoter-specific and regulatable fashion. Transcription initiated at the P1 promoter constitutively reads through the exon 1 block, whereas transcription for the P2 promoter can be modulated to either read through or be blocked. In normal cells, P2 is the predominant promoter. In contrast, in Burkitts's lymphoma (BL) cells, which are characterized by translocation that juxtapose c-myc and immunoglobulin (Ig) sequences, there is a shift of transcription initiation predominantly to the P1 promoter. Thus, the elongation block is abrogated in BL cells, resulting in high levels and/or constitutive synthesis of c-myc RNA. The investigator working hypothesis is that factors confer termination or antitermination activities to RNA polymerase II complexes in a promoter-specific fashion. These factors modify the polymerase complex to recognize or read through downstream block signals. In normal cells, this association is regulatable at the P2 promoter, where as the complex formed at the P1 promoter confers constitutive read through. In BL cells, the shift to P1 transcription may be due to the presence of trans-acting factors that suppress P2 activity and/or increase P1 utilization, or due to cis effects on promoter utilization and strength imposed by the proximity of the c-myc promoters to Ig sequences as a consequence of the translocation. The goal of this proposal is to identify the promoter-specific elements and trans-factors essential in conferring the read-through and "block" modes to polymerase II complexes transcribing the c-myc gene, and to determine the molecular basis of the abrogation of the c-myc elongation block and constitutive expression of c-myc in BL.