BOVINE ALPHA(S1)-CASEIN GENE-SEQUENCES DIRECT HIGH-LEVEL EXPRESSION OF HUMAN GRANULOCYTE-MACROPHAGE COLONY-STIMULATING FACTOR IN THE MILK OF TRANSGENIC MICE

The generation is reported of transgenic mice expressing human granulo cyte-macrophage colony-stimulating factor (GM-CSF) or human erythropoi etin (EPO) under the control of bovine alpha(s1)-casein regulatory seq uences. GM-CSF expression was specific to the mammary gland and levels of human GM-CSF in transgenic mouse milk were in the range of mg ml(- 1). The specific activity of the milk GM-CSF was similar to that of th e recombinant protein produced in Escherichia coli, and the glycosylat ion-derived size heterogeneity corresponded to that of the native huma n protein. In spite of the identical bovine regulatory sequences of th e fusion genes, the levels of human EPO in transgenic mouse milk were 10(3)-10(6) times lower than those of GM-CSF, ranging from 0.003 to 3 mu g ml(-1). There appeared to be a positive correlation between the a mount of EPO in the milk of lactating females and blood haematocrit va lues. In view of this, other type of constructs should be used to achi eve more efficient EPO expression and to circumvent concomitantly-occu rring adverse effects. In contrast, the high-level production of recom binant GM-CSF, its resemblance to the native mammalian protein, and mi ld adverse consequences of transgene expression imply that the current construct could be used for generation of larger GM-CSF transgenic an imals to produce this protein in quantities sufficient for therapeutic purposes.