Transcriptional repression by Pax5 (BSAP) through interaction with corepressors of the Groucho family

Pax5 (BSAP) functions as both a transcriptional activator and repressor dur ing midbrain patterning, B-cell development and lymphomagenesis. Here we de monstrate that Pax5 exerts its repression function by recruiting members of the Groucho corepressor family. In a yeast two-hybrid screen, the groucho- related gene product Grg4 was identified as a PaxS partner protein. Both pr oteins interact cooperatively via two separate domains: the N-terminal Q an d central SP regions of Grg4, and the octapeptide motif and C-terminal tran sactivation domain of PaxS. The phosphorylation state of Grg4 is altered in vivo upon Pax5 binding. Moreover, Grg4 efficiently represses the transcrip tional activity of PaxS in an octapeptide-dependent manner. Similar protein interactions resulting in transcriptional repression were observed between distantly related members of both the Pax2/5/8 and Groucho protein familie s. In agreement with this evolutionary conservation, the octapeptide motif of Pax proteins functions as a Groucho-dependent repression domain in Droso phila embryos, These data indicate that Pax proteins can be converted from transcriptional activators to repressors through interaction with corepress ors of the Groucho protein family.