C-Myc-independent restoration of multiple phenotypes by two C-Myc target genes with overlapping functions.
C-MYC, a transforming oncogene that is frequently overexpressed in many human cancers, regulates a variety of normal functions including cell cycle progression, apoptosis, and maintenance of cell size, morphology, and genomic integrity. Many target genes are modulated by c-Myc, and some can recapitulate a limited number of the above functions. Because most of these have been assessed in cells which also express endogenous c-Myc, however, it is not clear to what extent its proper regulation is also required. We show here that, in c-Myc nullizygous cells, two direct target genes, MT-MC1 and HMG-I, could each recapitulate multiple c-Myc phenotypes. Although these differ somewhat for the two genes, substantial overlap and cooperativity exist. The enforced expression of these two genes was also associated with the differential deregulation of some previously described c-Myc target genes, indicating the presence of a complex molecular circuitry. These observations argue that, despite the great diversity of gene regulation by c-Myc, many, although not all, of its functions can be phenocopied by a small subset of key downstream target genes. The approach described here should permit the identification of other target genes capable of further c-Myc-independent complementation.
Rothermund
Krisiti
K
Section of Hematology/Oncology, Children's Hospital of Pittsburgh.
Rogulski
Kenneth
K
Fernandes
Elaine
E
Whiting
Amy
A
Sedivy
John
J
Pu
Lixia
L
Prochownik
Edward V
EV
D000818:Animals; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D048708:Cell Growth Processes / Q000235:genetics; D002460:Cell Line; D048429:Cell Size; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D005786:Gene Expression Regulation; D016259:Genes, myc / Q000502:physiology*; D024243:HMGB1 Protein / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D006801:Humans; D051379:Mice; D009687:Nuclear Proteins; D010641:Phenotype; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D051381:Rats
D002352:Carrier Proteins; D024243:HMGB1 Protein; C458512:Myct1 protein, mouse; D009687:Nuclear Proteins; D016271:Proto-Oncogene Proteins c-myc