Invertebrate and vertebrate Runt-related proteins are transcription factors involved in the regulation of a variety of celldifferentiation events and aberrant functions of members of this protein family correlate with developmental abnormalities and neoplastic transformations (1-5). In particular, the mouse Runt-related protein, core-binding factor ␣2 (Cbfa2) 1 is essential for fetal liver hematopoiesis (6 -8) and its human homolog, AML1, is frequently targeted by chromosomal translocations that lead to acute myeloid leukemia (4, 6). A related mouse protein, Cbfa1, plays an essential role in osteoblast differentiation and mutations interfering with its function correlate with defects in ossification in mice and humans (3, 5, 9 -11). Studies in invertebrate and vertebrate species implicate Runt-related proteins in both transactivation and transcriptional repression, suggesting that their transcription functions may be regulated in context-dependent ways by interactions with other proteins (1, 9, 12-17). In this regard, Drosophila Runt has recently (18) been shown to interact with the protein Groucho, a general transcriptional repressor involved in a variety of gene regulatory events (19 -21). In particular, genetic studies show that repression of certain Runt-regulated genes is dependent on interaction with Groucho and is sensitive to Groucho dosage (18). These results implicate Groucho in the regulation of the transcriptional functions of Runt in Drosophila.A number of observations have suggested that the functions of mammalian Runt-related proteins are also modulated by Groucho homologs, designated as the transducin-like Enhancer of split (TLE) or Groucho-related gene products 1 through 4 (hereafter referred to as TLE1-4) (22-24). TLE proteins are co-expressed with the Runt-related proteins, Cbfa1 and Cbfa2/ AML1 (AML1), in a variety of cell types (7,14,(25)(26)(27). In addition, AML1 and TLE proteins can physically interact with each other (28). Furthermore, transient transfection studies in mammalian cells have shown that TLE proteins can inhibit the transactivation mediated by both Cbfa1 and AML1 (14,28,29). Together, these findings strongly suggest that TLE proteins are involved in the regulation of the transcriptional functions of mammalian Runt-related proteins.Studies in Drosophila have also implicated a second evolutionarily conserved family of transcription factors in the regulation of the functions of Runt-related proteins. Specifically, the basic helix loop helix proteins of the Drosophila Hairy/ Enhancer of split (HES) family are co-expressed with Groucho and Runt in a variety of cell types and physically interact with Groucho (18,20,21,30). Moreover, genetic studies in Drosophila show that runt and HES genes contribute to common gene regulatory events important for sex determination and segmentation (30 -32). Mammalian HES and runt-related genes are also co-expressed with TLE genes in a variety of cell types and their protein products participate in common developmental mechanisms (14,27,33,34). To...

Groucho is a Drosophila transcriptional repressor involved in neurogenesis, segmentation, and sex determination together with basic helix-loop-helix proteins of the Hairy/Enhancer of split (HES) family. Several mammalian Groucho homologues, the Transducin-like Enhancer of split (TLE) 1 through 4 proteins, share similar properties with their Drosophila counterpart, suggesting that TLE proteins perform functions analogous to the roles of Groucho in Drosophila. The aim of this study was to examine this possibility by characterizing the properties of TLE2 and extending the analysis of TLE1. It is shown here that TLE2 and TLE1 are transcriptional repressors that contain two separate repression domains, located either within a Gln-rich amino terminal region or within an internal domain characterized by an abundance of Ser, Thr, and Pro residues. In addition, both TLE2 and TLE1 can homo-and heterodimerize through a short region that is part of their amino-terminal transcription repression domains. Finally, TLE2 interacts and is co-expressed with mammalian HES proteins in both neural and non-neural tissues. Taken together, these findings implicate TLE2 in transcriptional repression and define the structural elements that mediate transcriptional and proteinϪprotein interaction functions of Groucho/TLE proteins.

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