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 involve d in regulation of proliferation, differentiation and apoptosis, c-Myc is a transcription factor that acts primarily by regulating the expression of o ther genes. However, it has been very difficult to identify bona fide c-Myc target genes that explain its diverse biological activities. The recent ge neration of c-myc deficient Rat1A fibroblasts with a profound and stable gr owth defect provides a new system to search for genes that can substitute f or c-myc in proliferation. In this study, we hale attempted to identify gen es that rescue the slow growth phenotype of c-myc null cells through introd uction of a series of potent cell cycle regulatory genes and several retrov iral cDNA expression libraries. None of the candidate genes tested, includi ng SV40 T-antigen and adenovirus E1A, caused reversal of the c-myc null gro wth 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 t he notion that there are no functional equivalents of the myc family of pro tooncogenes and also suggest that there are no c-Myc-activated gents that a lone can substitute for c-Myc in control of cell proliferation.