Cooperative interactions between HOX and PBX proteins mediated by a conserved peptide motif.
Homeoprotein products of the Hox/HOM gene family pattern the animal embryo through the transcriptional regulation of target genes. We have previously shown that the labial group protein HOXA-1 has intrinsically weak DNA-binding activity due to residues in the N-terminal arm of its homeodomain (M. L. Phelan, R. Sadoul, and M. S. Featherstone, Mol. Cell. Biol. 14:5066-5075, 1994). This observation, among others, suggests that HOX and HOM proteins require cofactors for stable interactions with DNA. We have demonstrated that a putative HOX cofactor, PBX1A, participates in cooperative DNA binding with HOXA-1 and the Deformed group protein HOXD-4. Three Abdominal-B class HOX proteins failed to cooperate with PBX1A. We mapped the interacting domain of HOXD-4 to the YPWMK 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 transcriptional activation domain of E2A with PBX1 creates an oncoprotein implicated in human pre-B-cell leukemias (M. P. Kamps, C. Murre, X.-H. Sun, and 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, Cell 60:535-545, 1990). A pentapeptide mutation that abolished cooperative interaction with PBX1A in vitro also abrogated synergistic transcriptional activation with the E2A/PBX oncoprotein. The direct contact of PBX family members by the HOX pentapeptide is likely to play an important role in developmental and oncogenic processes.
Phelan
M L
ML
McGill Cancer Centre, McGill University, Montreal, Québec, Canada.
Rambaldi
I
I
Featherstone
M S
MS
D000595:Amino Acid Sequence; D001483:Base Sequence; D017124:Conserved Sequence; D004247:DNA / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D015514:Oncogene Proteins, Fusion / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism*; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D011485:Protein Binding; D011487:Protein Conformation; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D015514:Oncogene Proteins, Fusion; D010446:Peptide Fragments; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; C083400:PBX1 protein, human; C072064:HOXD10 protein, human; C089847:E2A-Pbx1 fusion protein; D004247:DNA