EXPRESSION OF MAD, MXI1, MAX AND C-MYC DURING INDUCED-DIFFERENTIATIONOF HEMATOPOIETIC-CELLS - OPPOSITE REGULATION OF MAD AND C-MYC

The Myc proto-oncoprotein family is considered to play an important ro le in the control of cell growth and differentiation. It appears that the interaction of Myc with its heterodimeric partner Max is essential for Myc function. Recently two other partners of Max, called Mad and Mxi1, have been identified. In an effort to gain insight into the netw ork of these four proteins we have started to analyse the expression o f the c-myc, max, mad and mxi1 genes at the mRNA level during hematopo ietic cell growth and differentation. In the human myeloid cell lines U-937, HL-60 and ML-1 c-myc expression was down-regulated as shown pre viously after induction of differentiation, whereas the expression of max was only slightly affected. In contrast to these two genes the exp ression of mad was induced upon differentiation in the three cell line s by TPA, retinoic acid, vitamin D3, dimethyl sulfoxide, and interfero n-gamma and remained elevated for at least 3 days. A kinetic analysis showed that the induction of mad in U-937 in response to TPA was rapid (15 min) and at least in part transcriptional, reminiscent of immedia te early genes. The expression of mxi1 was induced in U-937 by some in ducers but not in HL-60 or ML-1. Its induction occurred slowly, peakin g around 48 h. These analysis thus suggest that the expression of mad and c-myc is inversely regulated during induced hematopoietic differen tiation.