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.
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