In Drosophila, the development of the compound eye depends on the movement of a morphogenetic furrow (MF) from the posterior (P) to the anterior (A) of the eye imaginal disc. We define several subdomains along the A-P axis of the eye disc that express distinct combinations of transcription factors. One subdomain, anterior to the MF, expresses two homeobox genes, eyeless (ey) and homothorax (hth), and the zinc-finger gene teashirt (tsh). We provide evidence that this combination of transcription factors may function as a complex and that it plays at least two roles in eye development: it blocks the expression of later-acting transcription factors in the eye development cascade, and it promotes cell proliferation. A key step in the transition from an immature proliferative state to a committed state in eye development is the repression of hth by the BMP-4 homolog Decapentaplegic (Dpp).
The Notch signaling pathway relies on a proteolytic cascade to release its transcriptionally active intracellular domain, on force to unfold a protective domain and permit proteolysis, on extracellular domain glycosylation to tune the forces exerted by endocytosed ligands, and on a motley crew of nuclear proteins, chromatin modifiers, ubiquitin ligases, and a few kinases to regulate activity and half-life. Herein we provide a review of recent molecular insights into how Notch signals are triggered and how cell shape affects these events, and use the new insights to illuminate a few perplexing observations.
Sp1-like zinc finger transcription factors are involved in the regulation of cell growth and differentiation. Recent evidence demonstrating that mammalian cells express novel, yet uncharacterized, Sp1-like proteins has stimulated a search for new members of this family. We and others have recently reported that the transforming growth factor (TGF)--regulated gene TIEG encodes a new Sp1-like protein that inhibits cell growth in cultured cells. Here we report the identification, nuclear localization, DNA binding activity, transcriptional repression activity, and growth inhibitory effects of TIEG2, a novel TGF--inducible gene related to TIEG. TIEG2 is ubiquitously expressed in human tissues, with an enrichment in pancreas and muscle. TIEG2 shares 91% homology with TIEG1 within the zinc finger region and 44% homology within the N terminus. Biochemical characterization reveals that TIEG2 is a nuclear protein, which, as predicted from the primary structure, specifically binds to an Sp1-like DNA sequence in vitro and can repress a promoter containing Sp1-like binding sites in transfected Chinese hamster ovary epithelial cells. Furthermore, functional studies using [ The transcription factor Sp1 is the founding member of a family of zinc finger proteins that regulate a variety of genes involved in cell growth and differentiation (1-22). Sp1-like binding sites, for example, are critical for the expression of a large group of genes necessary for DNA synthesis and cell cycle progression (2, 14 -22). In addition, the overexpression of some members of the Sp1-like family of proteins in cultured cells has been shown to induce cell proliferation, cell cycle arrest, or apoptosis (9, 10, 13, 23). Furthermore, the disruption of Sp1 by homologous recombination demonstrates that at least some members of this subfamily of proteins are essential for normal development in vivo (24). Thus, Sp1-like proteins are emerging as critical regulators of the cellular events underlying morphogenesis.The current members within the Sp1-like family of proteins include Sp1, Sp2, Sp3, Sp4, BTEB1, BTEB2, CPBP, BKLF, EKLF, GKLF, LKLF, and TIEG 1 (1, 3-15). These proteins are characterized by the presence of three highly conserved Cterminal zinc finger domains, which bind to GC-rich sequences. The growth regulatory effects of these proteins are believed to be mediated by the tight regulation of a hierarchical cascade of gene expression resulting from their binding to cis-regulatory GC-rich sites and subsequent interaction with the basal transcriptional machinery (25)(26)(27)(28)(29). In several instances, the identity of the specific Sp1-like protein that regulates distinct promoters through GC-rich sequences has been determined (5, 7, 14 -22). However, emerging evidence reveals that GC-rich sequences in other promoters bind to as yet uncharacterized proteins (22, 30 -36). This evidence has led many laboratories to search for novel members of the Sp1-like proteins. We and others, for example, have recently reported that the TIEG gene encodes an Sp1-li...
During Drosophila embryogenesis, segments, each with an anterior and posterior compartment, are generated by the segmentation genes while the Hox genes provide each segment with a unique identity. These two processes have been thought to occur independently. Here we show that abdominal Hox proteins work directly with two different segmentation proteins, Sloppy paired and Engrailed, to repress the Hox target gene Distalless in anterior and posterior compartments, respectively. These results suggest that segmentation proteins can function as Hox cofactors and reveal a previously unanticipated use of compartments for gene regulation by Hox proteins. Our results suggest that these two classes of proteins may collaborate to directly control gene expression at many downstream target genes.
In Drosophila, differences between segments, such as the presence or absence of appendages, are controlled by Hox transcription factors. The Hox protein Ultrabithorax (Ubx) suppresses limb formation in the abdomen by repressing the leg selector gene Distalless, whereas Antennapedia (Antp), a thoracic Hox protein, does not repress Distalless. We show that the Hox cofactors Extradenticle and Homothorax selectively enhance Ubx, but not Antp, binding to a Distalless regulatory sequence. A C-terminal peptide in Ubx stimulates binding to this site. However, DNA binding is not sufficient for Distalless repression. Instead, an additional alternatively spliced domain in Ubx is required for Distalless repression but not DNA binding. Thus, the functional specificities of Hox proteins depend on both DNA binding-dependent and -independent mechanisms.
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