YY1 CAN INHIBIT C-MYC FUNCTION THROUGH A MECHANISM REQUIRING DNA-BINDING OF YY1 BUT NEITHER ITS TRANSACTIVATION DOMAIN NOR DIRECT INTERACTION WITH C-MYC

The proto-oncoprotein c-Myc and the multifunctional transcriptional re gulator YY1 have been shown previously to interact directly in a manne r that excludes Max from the complex (Shrivastava et al., 1993). As bi nding to Max is necessary for all known c-Myc activities we have analy sed the influence of YY1 on c-Myc function. We demonstrate that YY1 is a potent inhibitor of c-Myc transforming activity. The region in YY1 required for inhibition corresponds to a functional DNA-binding domain and is distinct from the domains necessary for direct binding to c-My c. Furthermore the transactivation domain of YY1 was not necessary sug gesting that gene regulation by YY1, for example through DNA bending o r displacement of regulators from DNA, could be the cause for the nega tive regulation of c-Myc. This model of indirect regulation of c-Myc b y YY1 was supported by the finding that although YY1 did not bind to t he c-Myc transactivation domain (TAD) in vitro it was able to inhibit transactivation by Gal4-MycTAD fusion proteins in transient transfecti ons. As for the inhibition of transformation, an intact DNA-binding do main of YY1 was necessary and sufficient for this effect. In addition YY1 did not alter c-Myc/Max DNA binding, further supporting an indirec t mode of action. Our findings point to a role of YY1 as a negative re gulator of cell growth with a possible involvement in tumor suppressio n.