CELLULAR PROLIFERATION AND TRANSFORMATION-INDUCED BY HOXB4 AND HOXB3 PROTEINS INVOLVES COOPERATION WITH PBX1

The products of PBX homeobox genes, which mere initially discovered in reciprocal translocations occurring in human leukemias, have been sho wn to cooperate in the in vitro DNA binding with HOX proteins. Despite the growing body of data implicating Hox genes in the development of various cancers, little is known about the role of HOX-PBX interaction s in the regulation of proliferation and induction of transformation o f mammalian cells. We build on the existing model of Hox-induced trans formation of Rat-1 cells to show that both cellular transformation and proliferation induced by Hoxb4 and Hoxb3 are greatly modulated by the levels of available PBX1 present in these cells. Furthermore, we show that the transforming capacity of these two HOX proteins depends on t heir conserved tetrapeptide and homeodomain regions which mediate bind ing to PBX and DNA, respectively. Taken together, results of this stud y demonstrate that cooperation between HOX and PBX proteins modulates cellular proliferation and strongly suggest that cooperative DIVA bind ing by these two groups of proteins represent the basis for Hox-induce d cellular transformation.