Two regulatory domains are required for downregulation of c-myc transcription in differentiating U937 cells.
In many differentiating cells, a reduction of c-myc proto-oncogene expression is a prerequisite for terminal differentiation. The downmodulation of c-myc in differentiating cells is due to at least two different mechanisms: (i) an elongation block to c-myc transcription activated during an early phase of differentiation and (ii) an inhibition of transcription initiation activated during a later phase. In order to determine cis-acting target structures of the c-myc gene required for the late-phase downregulation of transcriptional initiation, we permanently transfected U937 cells with constructs containing the bacterial chloramphenicol acetyl transferase (CAT) gene driven by a 2.8 kb c-myc promoter region or deletions thereof. We determined two distinct domains in the c-myc promoter region both of which are essential for efficient terminal downregulation: a proximal domain and a distal domain which are located between base pairs -606 to -101, and between -2392 to -1396, respectively, relative to P1. The identification of two distinct regulatory elements suggests the requirement and cooperation of two regulatory factors as an essential event for mediating differentiation-induced downregulation of c-myc in monocytic cells. The implications of these results for deregulation of the translocated c-myc allele in Burkitt's lymphoma are discussed.
Skerka
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Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany.
Zipfel
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Siebenlist
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D002454:Cell Differentiation; D015500:Chloramphenicol O-Acetyltransferase / Q000235:genetics; D015536:Down-Regulation; D005809:Genes, Regulator; D016259:Genes, myc; D006801:Humans; D007948:Leukemia, Monocytic, Acute / Q000235:genetics / Q000473:pathology; D011401:Promoter Regions, Genetic; D000090063:Proto-Oncogene Mas; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured
C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D015500:Chloramphenicol O-Acetyltransferase