Ultrabithorax protein is necessary but not sufficient for full activation of decapentaplegic expression in the visceral mesoderm.

Sun, Bryan K.; Hursh, Deborah A.; Jackson, Donald; Beachy, Philip A.

doi:10.1002/j.1460-2075.1995.tb07028.x

Cited by 78 publications

(68 citation statements)

References 56 publications

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“…bxd is a 40-kb region of BX-C, immediately upstream from the Ultrabithorax (Ubx) unit, and capable of exerting cis-regulatory control over expression of this unit (Lipshitz et al, 1987). It had already been shown that the TGF␤ superfamily member Dpp stimulated transcription of Ubx and that the Ubx protein was necessary but not sufficient for full activation of dpp expression (Mathies et al, 1994;Sun et al, 1995;Eresh et al, 1997). Thus, it was conceivable that a homologue of the regulatory region of Ubx might be important in TGF␤ signaling.…”

Section: Resultsmentioning

confidence: 99%

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A Novel Transforming Growth Factor-β Receptor-interacting Protein That Is Also a Light Chain of the Motor Protein Dynein

Tang¹,

Staub²,

Gao

et al. 2002

MBoC

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The phosphorylated, activated cytoplasmic domains of the transforming growth factor-␤ (TGF␤) receptors were used as probes to screen an expression library that was prepared from a highly TGF␤-responsive intestinal epithelial cell line. One of the TGF␤ receptor-interacting proteins isolated was identified to be the mammalian homologue of the LC7 family (mLC7) of dynein light chains (DLCs). This 11-kDa cytoplasmic protein interacts with the TGF␤ receptor complex intracellularly and is phosphorylated on serine residues after ligand-receptor engagement. Forced expression of mLC7-1 induces specific TGF␤ responses, including an activation of Jun N-terminal kinase (JNK), a phosphorylation of c-Jun, and an inhibition of cell growth. Furthermore, TGF␤ induces the recruitment of mLC7-1 to the intermediate chain of dynein. A kinase-deficient form of TGF␤ RII prevents both mLC7-1 phosphorylation and interaction with the dynein intermediate chain (DIC). This is the first demonstration of a link between cytoplasmic dynein and a natural growth inhibitory cytokine. Furthermore, our results suggest that TGF␤ pathway components may use a motor protein light chain as a receptor for the recruitment and transport of specific cargo along microtublules. INTRODUCTIONTransforming growth factor-␤ (TGF␤) is the prototype for the TGF␤ superfamily of highly conserved growth regulatory polypeptides that also includes the activins, inhibins, bone morphogenetic proteins, decapentaplegic (Dpp), nodal, Lefty, and others (Roberts, 1998;Sporn and Vilcek, 2000;Yue and Mulder, 2001). Alterations in the TGF␤ signaling components and pathways have been implicated in a vast array of human pathologies, including cancer (Massague et al., 2000;Sporn and Vilcek, 2000;Derynck et al., 2001).TGF␤ binds to two types of transmembrane serine/threonine kinase receptors (RI and RII) in a heterotetrameric complex, to activate downstream components (Roberts, 1998; Massague et al., 2000;Sporn and Vilcek, 2000;Yue and Mulder, 2001). The Smad family of signaling intermediates plays an important role in mediating TGF␤ responses (Attisano and Wrana, 2000;ten Dijke et al., 2000;Yue and Mulder, 2001). Moreover, TGF␤ has been shown to regulate Ras (Mulder and Morris, 1992;Hartsough et al., 1996;Yue et al., 1998) and several components of the mitogen-activated protein kinase (Mapk) pathways (Hartsough and Mulder, 1995;Frey and Mulder, 1997;Mulder, 2000;Sporn and Vilcek, 2000;Yue and Mulder, 2001). In addition to the Ras/Mapk and Smad pathways, several proteins have been identified based upon their interaction with the TGF␤ receptors (Yue and Mulder, 2001). Furthermore, various Smad-interacting proteins have also been identified, including SARA and Dab2, which interact with both Smads and the TGF␤ receptors (Tsukazaki et al., 1998;Hocevar et al., 2001;Yue and Mulder, 2001).Despite advances in our understanding of the mechanisms by which the Smad and Ras/Mapk cascades mediate some TGF␤ effects, these pathways seem to regulate primarily transcriptional events (Hocevar et al., 1...

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Section: Resultsmentioning

confidence: 99%

“…but not sufficient for full activation of dpp expression (Mathies et al, 1994;Sun et al, 1995;Eresh et al, 1997). Thus, it was conceivable that a homologue of the regulatory region of Ubx might be important in TGF␤ signaling.…”

Section: Molecular Biology Of the Cell 4486mentioning

confidence: 99%

A Novel Transforming Growth Factor-β Receptor-interacting Protein That Is Also a Light Chain of the Motor Protein Dynein

Tang¹,

Staub²,

Gao

et al. 2002

MBoC

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“…For example, genetic studies have demonstrated that full activation of the Drosophila decapentaplegic (dpp) gene depends on the presence of both, Ultrabithorax (Ubx, a Hox gene homolog) and extradenticle (exd, a homolog of PBX1) (Sun et al, 1995;Chan et al, 1994). Furthermore, it was shown that the YPWM motif of Hoxa5 is essential for the biological speci®city of this gene (Zhao et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

Cellular proliferation and transformation induced by HOXB4 and HOXB3 proteins involves cooperation with PBX1

et al. 1998

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The products of PBX homeobox genes, which were initially discovered in reciprocal translocations occurring in human leukemias, have been shown to cooperate in the in vitro DNA binding with HOX proteins. Despite the growing body of data implicating Hox genes in the development of various cancers, little is known about the role of HOX ± PBX interactions in the regulation of proliferation and induction of transformation of mammalian cells. We build on the existing model of Hoxinduced transformation of Rat-1 cells to show that both cellular transformation and proliferation induced by Hoxb4 and Hoxb3 are greatly modulated by the levels of available PBX1 present in these cells. Furthermore, we show that the transforming capacity of these two HOX proteins depends on their conserved tetrapeptide and homeodomain regions which mediate binding to PBX and DNA, respectively. Taken together, results of this study demonstrate that cooperation between HOX and PBX proteins modulates cellular proliferation and strongly suggest that cooperative DNA binding by these two groups of proteins represent the basis for Hoxinduced cellular transformation.

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“…The dppVM enhancer A 419-bp genomic segment, located 9 kilobases (kb) upstream of the coding sequence of the dpp gene, is capable of driving reporter gene expression in dpp-positive cells in parasegment 7 of the embryonic visceral mesoderm 36,37 ( Fig. 2B).…”

Section: Reverse-engineering a Transcriptional Enhancermentioning

confidence: 99%

“…(B) Embryos carrying the wild-type, 419-bp dppVM in the Ganesh-Z1 vector, 30 tains predicted binding sites for the Hox protein Ultrabithorax (Ubx) and its cofactor Extradenticle (Exd), the Wnt-responsive factor TCF, and the FoxF-related factor Biniou (Bin); all four proteins directly bind to dppVM in vitro. [37][38][39] Ubx and Exd directly activate transcription via dppVM, 37,40 while TCF acts as a Wnt-regulated transcriptional switch, activating dpp in Wnt-responding visceral mesoderm cells and repressing dpp in cells not receiving Wnt signaling. 38 However, neither ectopic Ubx/Exd nor ectopic Wnt signaling is sufficient to drive enhancer expression outside the visceral mesoderm, and dppVM is not active in other Wnt-responding or Ubx/Exd-expressing cells.…”

Section: Reverse-engineering a Transcriptional Enhancermentioning

confidence: 99%

Reverse-Engineering a Transcriptional Enhancer: A Case Study inDrosophila

Johnson

Zhao

Golden

et al. 2008

Tissue Engineering Part A

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Enhancers, or cis-regulatory elements, are the principal determinants of spatiotemporal patterning of gene expression. For reasons of clinical and research utility, it is desirable to build customized enhancers that drive novel gene expression patterns, but currently, we largely rely on ''found'' genomic elements. Synthetic enhancers, assembled from transcription factor binding sites taken from natural signal-regulated enhancers, generally fail to behave like their wild-type counterparts when placed in transgenic animals, suggesting that important aspects of enhancer function are still unexplored. As a step toward the creation of a truly synthetic regulatory element, we have undertaken an extensive structure-function study of an enhancer of the Drosophila decapentaplegic (dpp) gene that drives expression in the developing visceral mesoderm (VM). Although considerable past efforts have been made to dissect the dppVM enhancer, transgenic experiments presented here indicate that its activity cannot be explained by the known regulators alone. dppVM contains multiple, previously uncharacterized, regulatory sites, some of which exhibit functional redundancy. The results presented here suggest that even the best-studied enhancers must be further dissected before they can be fully understood, and before faithful synthetic elements based on them can be created. Implications for developmental genetics, mathematical modeling, and therapeutic applications are discussed.

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Ultrabithorax protein is necessary but not sufficient for full activation of decapentaplegic expression in the visceral mesoderm.

Cited by 78 publications

References 56 publications

A Novel Transforming Growth Factor-β Receptor-interacting Protein That Is Also a Light Chain of the Motor Protein Dynein

A Novel Transforming Growth Factor-β Receptor-interacting Protein That Is Also a Light Chain of the Motor Protein Dynein

Cellular proliferation and transformation induced by HOXB4 and HOXB3 proteins involves cooperation with PBX1

Reverse-Engineering a Transcriptional Enhancer: A Case Study inDrosophila

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