COOPERATIVE INTERACTIONS BETWEEN HOX AND PBX PROTEINS MEDIATED BY A CONSERVED PEPTIDE MOTIF

Homeoprotein products of the Hox/HOM gene family pattern the animal em bryo through the transcriptional regulation of target genes, We have p reviously shown that the labial group protein HOXA-1 has intrinsically weak DNA-binding activity due to residues in the N-terminal arm of it s homeodomain (M. L. Phelan, R. Sadoul, and M. S. Featherstone, Mol. C ell. Biol. 14:5066-5075, 1994), This observation, among others, sugges ts that HOX and HOM proteins require cofactors for stable interactions with DNA, We have demonstrated that a putative HOX cofactor, PBX1A, p articipates in cooperative DNA binding with HOXA-1 and the Deformed gr oup protein HOXD-4. Three Abdominal-B class HOX proteins failed to coo perate with PBX1A, We mapped the interacting domain of HOXD-4 to the Y PWMK pentapeptide motif, a conserved sequence found N terminal to the homeodomain of HOXA-1 and many other homeoproteins but absent from the Abdominal-B class, The naturally occurring fusion of the transcriptio nal activation domain of E2A with PBX1 creates an oncoprotein implicat ed in human pre-B-cell leukemias (M. P. Kamps, C. Murre, X.-H. Sun, an d D. Baltimore, Cell 60:547-555, 1990; J. Nourse, J. D. Mellentin, N. Galili, J. Wilkinson, E. Starbridge, S. D. Smith, and M. L. Cleary, Ce ll 60:535-545, 1990), A pentapeptide mutation that abolished cooperati ve interaction with PBX1A in vitro also abrogated synergistic transcri ptional activation with the E2A/PBX oncoprotein, The direct contact of PBX family members by the HOX pentapeptide is likely to play an impor tant role in developmental and oncogenic processes.