A genetic screen to identify genes that rescue the slow growth phenotype of c-myc null fibroblasts.
The c-myc gene is frequently over-expressed in human cancers and is involved in regulation of proliferation, differentiation and apoptosis. c-Myc is a transcription factor that acts primarily by regulating the expression of other genes. However, it has been very difficult to identify bona fide c-Myc target genes that explain its diverse biological activities. The recent generation of c-myc deficient Rat1A fibroblasts with a profound and stable growth defect provides a new system to search for genes that can substitute for c-myc in proliferation. In this study, we have attempted to identify genes that rescue the slow growth phenotype of c-myc null cells through introduction of a series of potent cell cycle regulatory genes and several retroviral cDNA expression libraries. None of the candidate genes tested, including SV40 T-antigen and adenovirus E1A, caused reversal of the c-myc null growth defect. Furthermore, extensive screens with high-complexity retroviral cDNA libraries from three different tissue sources revealed that only c-myc and N-myc rescued the c-myc null slow-growth phenotype. Our data support the notion that there are no functional equivalents of the myc family of proto-oncogenes and also suggest that there are no c-Myc-activated genes that alone can substitute for c-Myc in control of cell proliferation.
Division of Molecular Carcinogenesis, and Center for Biomedical Genetics, The Netherlands Cancer Institute, Amsterdam.
K
K
Berns
E M
EM
Hijmans
E
E
Koh
G Q
GQ
Daley
R
R
Bernards
D017500:Adenovirus E1A Proteins / Q000235:genetics; D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000235:genetics; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D002455:Cell Division / Q000235:genetics; D002460:Cell Line; D019938:Cyclin D1 / Q000235:genetics; D019927:Cyclin E / Q000235:genetics; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050703:E2F2 Transcription Factor; D050699:E2F3 Transcription Factor; D005347:Fibroblasts / Q000166:cytology*; D018257:Helix-Loop-Helix Motifs; D006801:Humans; D020014:K562 Cells; D016350:Leucine Zippers; D051379:Mice; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051381:Rats; D056465:Retinoblastoma-Binding Protein 1; D050680:Transcription Factor DP1; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
D017500:Adenovirus E1A Proteins; D000952:Antigens, Polyomavirus Transforming; C533431:Arid4a protein, mouse; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D019927:Cyclin E; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050703:E2F2 Transcription Factor; D050699:E2F3 Transcription Factor; C098319:E2F3 protein, human; C490840:E2f3 protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D056465:Retinoblastoma-Binding Protein 1; D050680:Transcription Factor DP1; D014157:Transcription Factors; D019938:Cyclin D1