Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.8 (FAST)
 758 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have examined the role of the maternally encoded transcription factor FAST-1 in the establishment of the mesodermal transcriptional program in Xenopus embryos. FAST-1 has been shown to associate with Smad2 and Smad4, transducers of TGFbeta superfamily signals, in response to stimulation by several TGFbeta superfamily ligands. The FAST-1/Smad2/Smad4 complex binds and activates a 50 bp activin responsive element identified in the promoter of the meso-endodermal marker Mix.2. We have now used three complementary approaches to demonstrate that FAST-1 is a central regulator of mesoderm induction by ectopic TGFbeta superfamily ligands and during endogenous patterning: ectopic expression of mutationally activated FAST-1, ectopic expression of dominant inhibitory FAST-1, and injection of a blocking antibody specific for FAST-1. Expression of constitutively transcriptionally active FAST-1 fusion protein (FAST-VP16(A)) in prospective ectoderm can directly induce the same set of general and dorsal mesodermal genes, as well as some endodermal genes, as are induced by activin or Vg1. In intact embryos, this construct can induce secondary axes similar to those induced by activin or Vg1. Conversely, expression of a FAST-1-repressor fusion (FAST-En(R)) in prospective ectoderm blocks induction of mesodermal genes by activin, while expression of FAST-En(R) in intact embryos prevents general/dorsal mesodermal gene expression and axial development. Injection of a blocking antibody specific for FAST-1 prevents induction of mesodermal response genes by activin or Vg1, but not by FGF. In intact embryos, this antibody can prevent the expression of early mesodermal markers and inhibit axis formation, demonstrating that FAST-1 is a necessary component of the first steps in the specification of mesoderm.
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PMID:FAST-1 is a key maternal effector of mesoderm inducers in the early Xenopus embryo. 1057 39

The Smad family of proteins are critical components of the TGFbeta superfamily signalling pathway. Ligand addition induces phosphorylation of specific receptor-regulated Smads, which then form heteromeric complexes with the common mediator Smad, Smad4. This complex then translocates from the cytoplasm into the nucleus. Once there, the R-Smad/Smad4 complex interacts with a variety of DNA binding proteins and is thereby targetted to a diverse array of gene promoters. The Smad-containing DNA binding complex can then positively or negatively regulate gene expression through the recruitment of co-activators and co-repressors. Xenopus FAST (now known as FoxH1) was the first Smad DNA binding partner identified and the FoxH1 family now includes related proteins from mouse, human and Zebrafish. In all organisms examined, FoxH1 is expressed primarily during the earliest stages of development and thus FoxH1 is thought to play a critical role in mediating TGFbeta superfamily signals during these early developmental stages. Other Smad partners range from those that are ubiquitously expressed to others that are present only in specific cell types or developmental stages. Thus, it is the interaction of Smads with a wide range of specific transcriptional partners that is important for the generation of diverse biological responses to TGFbeta superfamily members.
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PMID:The transcriptional role of Smads and FAST (FoxH1) in TGFbeta and activin signalling. 1145 66

FAST and Runx (CBFa) transcription factors, which are expressed during specific phases of embryogenesis and tissue patterning, bind directly to Smad proteins and integrate effects induced by various TGF-beta gene family members. The DNA binding sequences for FAST and Runx differ only minimally. The isoform Runx2 (previously termed CBFa1) is highly expressed by osteoblasts and regulates expression of the TGF-beta receptor I in these cells. Here we show that FAST-dependent transcription is endogenously restricted in osteoblasts but can be significantly enhanced by disruption of Runx2 expression. Native and synthetic Runx2 bind to both Runx and FAST binding sequences, whereas FAST-1 efficiently binds only to the FAST binding sequence. However, overexpression of FAST-1 potently suppresses TGF-beta receptor I gene expression in osteoblasts and thereby reduces TGF-beta activity independently of competing for Runx2 at the level of DNA binding. These results provide a new example of how nuclear factors associated with specific developmental states or tissue lineages may influence TGF-beta-dependent events in restricted ways.
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PMID:Control and counter-control of TGF-beta activity through FAST and Runx (CBFa) transcriptional elements in osteoblasts. 1151 65