THE GADD AND MYD GENES DEFINE A NOVEL SET OF MAMMALIAN GENES ENCODINGACIDIC PROTEINS THAT SYNERGISTICALLY SUPPRESS CELL-GROWTH

A remarkable overlap was observed between the gadd genes, a group of o ften coordinately expressed genes that are induced by genotoxic stress and certain other growth arrest signals, and the MyD genes, a set of myeloid differentiation primary response genes. The MyD116 gene was fo und to be the murine homolog of the hamster gadd34 gene, whereas MyD11 8 and gadd45 were found to represent two separate but closely related genes. Furthermore, gadd34/MyD116, gadd45, MyD118, and gadd153 encode acidic proteins with very similar and unusual charge characteristics; both this property and a similar pattern of induction are shared with mdm2, which, like gadd45, has been shown previously to be regulated by the tumor suppressor p53. Expression analysis revealed that they are distinguished from other growth arrest genes in that they are DNA dama ge inducible and suggests a role for these genes in growth arrest and apoptosis either coupled with or uncoupled from terminal differentiati on. Evidence is also presented for coordinate induction in vivo by str ess. The use of a short-term transfection assay, in which expression v ectors for one or a combination of these gadd/MyD genes were transfect ed with a selectable marker into several different human tumor cell li nes, provided direct evidence for the growth-inhibitory functions of t he products of these genes and their ability to synergistically suppre ss growth. Taken together, these observations indicate that these gene s define a novel class of mammalian genes encoding acidic proteins inv olved in the control of cellular growth.