Abstract
Drosophila Runt is the founding member of a family of related transcription factors involved in the regulation of a variety of cell-differentiation events in invertebrates and vertebrates. Runt-related proteins act as both transactivators and transcriptional repressors, suggesting that context-dependent mechanisms modulate their transcriptional properties. The aim of this study was to elucidate the molecular mechanisms that contribute to the regulation of the functions of the mammalian Runt-related protein, Cbfa1. Here we provide the first demonstration that Cbfa1 (as well as the related protein, Cbfa2/AML1) physically interacts with the basic helix loop helix transcription factor, HES-1, a mammalian counterpart of the Drosophila Hairy and Enhancer of split proteins. This interaction is mediated by the carboxyl-terminal domains of Cbfa1 and HES-1, but does not require their respective tetrapeptide motifs, WRPY and WRPW. Our studies also show that HES-1 can antagonize the binding of Cbfa1 to mammalian transcriptional corepressors of the Groucho family. Moreover, HES-1 can potentiate Cbfa1-mediated transactivation in transfected cells. Taken together, these findings implicate HES-1 in the transcriptional functions of Cbfa1 and suggest that the concerted activities of Groucho and HES proteins modulate the functions of mammalian Runt-related proteins.
Highlights
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)
Genetic studies in Drosophila show that runt and Hairy/ Enhancer of split (HES) genes contribute to common gene regulatory events important for sex determination and segmentation (30 –32)
HES-1 Physically Interacts with Cbfa[1] and AML1—Based on the participation of runt and HES genes in common developmental pathways in Drosophila (30 –32) and the shared ability of both HES and Runt-related proteins to bind to transcriptional corepressors of the Groucho/transducin-like Enhancer of split (TLE) family (14, 18, 21, 28, 36), we asked whether specific mammalian HES and Runtrelated proteins might associate with each other
Summary
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). 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). Transient transfection studies in mammalian cells have shown that TLE proteins can inhibit the transactivation mediated by both Cbfa[1] 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. Mammalian HES and runt-related genes are co-expressed with TLE genes in a variety of cell types and their protein products participate in common developmental mechanisms (14, 27, 33, 34) Together, these findings raise the possibility that Runt-related and HES proteins may interact
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