OPTIMAL ACTIVATION OF AN ENDOGENOUS GENE BY HOX11 REQUIRES THE NH2-TERMINAL-50 AMINO-ACIDS

The HOX11 homeobox gene was first identified through studies of the t( 7;10) and t(10;14) chromosomal translocations of acute T cell leukemia . In addition, analysis of Hox11(-/-) mice has demonstrated a critical role for this gene in murine spleen development. A possible mode of i n vivo function for the HOX11 protein in these two situations is regul ation of target genes following DNA binding via the homeodomain, but l ittle is known about how HOX11 regulates transcription in vivo. By per forming transcriptional studies in yeast and mammalian one-hybrid syst ems, a modular transcriptional transactivation region at the NH2 termi nus of HOX11 has been functionally dissected from other parts of the p rotein. This NH2-terminal region includes the previously identified sh ort conserved Hep motif, which itself activates transcription in one-h ybrid assays. The importance of the NH2-terminal region for the functi on of HOX11 in vivo was assayed by activating a HOX11-dependent gene i n NIH 3T3 cells. Activation of this gene was found to be dependent upo n an intact homeodomain in HOX11, but maximal activation was obtained only when the NH2-terminal 50 amino acids of HOX11 was present, showin g that this region of HOX11 is important for in vivo transcriptional c ontrol of a chromosomal target gene.