The Tal1 oncoprotein inhibits E47-mediated transcription - Mechanism of inhibition

The Tall oncogene is a class II basic helix-loop-helix (bHLH) transcription factor, overexpressed in as much as 60% of T cell acute lymphoblastic leukemia cases. Like other class II bHLH proteins, Tall can heterodimerize with the class I bHLH proteins, such as E47, and bind to a DNA recognition sequence termed E box. Therefore, it is believed that the oncogenic capacity of Tall lies in its ability, as a heterodimer with E47, to activate aberrantly a set of "leukemogenic" genes in T cells. However, compared with E47 homodimers, Tal1/E47 heterodimers are very poor transactivators. Thus the effect of Tall is actually to inhibit E47 homodimer activity. Here we propose that the transforming properties of Tall are the result of its ability to inhibit E47 activity. We address the mechanism of Tall inhibition and demonstrate that Tal1/E47 heterodimers cannot activate transcription because their respective activation domains are incompatible. Furthermore, we present data showing that Tall can inhibit E47-mediated activation of the CIP1 gene. Finally, we demonstrate that Tall inhibits E47 activity in leukemic T cells.