Deregulation of common genes by c-Myc and its direct target, MT-MC1.
In addition to its role in cancer, the c-Myc oncoprotein controls many normal cellular processes as a consequence of its function as a basic helix-loop-helix leucine zipper transcription factor. Determining which of the myriad genes under c-Myc control are relevant for these various roles is thus a major challenge. mt-mc1 is a direct c-Myc target gene whose overexpression recapitulates multiple c-Myc phenotypes, including transformation. Using transcriptional profiling, we now show that MT-MC1-overexpressing myeloid cells misregulate a total of 47 distinct transcripts, a large proportion of which are involved in signal transduction and/or cancer. Analysis of these genes reveals a consensus promoter structure consisting of multiple, often closely spaced c-Myc binding sites and three additional Wilm's tumor and Egr1-like motifs. More than one-third of MT-MC1 target genes are also clustered on six cancer-associated chromosomal loci. Most surprisingly, all of the transcripts examined also are regulated by c-Myc. Finally, an estrogen receptor-MT-MC1 fusion protein was used to establish that all examined transcripts were regulated directly by the chimeric protein. Our results thus indicate that MT-MC1 target genes largely comprise a subset of those regulated by c-Myc. We propose that the properties imparted by MT-MC1 are the result of its control of a small and select c-Myc target gene population.
Rogulski
Kenneth R
KR
Section of Hematology/Oncology, Children's Hospital of Pittsburgh, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA 15213, USA.
Cohen
Debra E
DE
Corcoran
David L
DL
Benos
Panayiotis V
PV
Prochownik
Edward V
EV
D020816:Amino Acid Motifs; D000818:Animals; D001665:Binding Sites; D015153:Blotting, Western; D002352:Carrier Proteins / Q000096:biosynthesis* / Q000737:chemistry; D002460:Cell Line; D002874:Chromosome Mapping; D002875:Chromosomes / Q000648:ultrastructure; D005786:Gene Expression Regulation; D016259:Genes, myc; D005822:Genetic Vectors; D006801:Humans; D016350:Leucine Zippers; D051379:Mice; D008954:Models, Biological; D009154:Mutation; D009687:Nuclear Proteins; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D010957:Plasmids / Q000378:metabolism; D011401:Promoter Regions, Genetic; D016271:Proto-Oncogene Proteins c-myc / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011960:Receptors, Estrogen / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D012984:Software; D014158:Transcription, Genetic
D002352:Carrier Proteins; C458512:Myct1 protein, mouse; D009687:Nuclear Proteins; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D011960:Receptors, Estrogen