A WW domain protein TAZ is a critical coactivator for TBX5, a transcription factor implicated in Holt–Oram syndrome

Abstract

The T-box transcription factor TBX5 plays essential roles in cardiac and limb development. Various mutations in the TBX5 gene have been identified in patients with Holt-Oram syndrome, which is characterized by congenital defects in the heart and upper extremities. In this study, we identified a WW-domain-containing transcriptional regulator TAZ as a potent TBX5 coactivator. TAZ directly associates with TBX5 and markedly stimulates TBX5-dependent promoters by interacting with the histone acetyltransferases p300 and PCAF. YAP, a TAZ-related protein with conserved functional domains, also stimulates TBX5-dependent transcription, possibly by forming a heterodimer with TAZ. TBX5 lacks a PY motif, which mediates the association of other proteins with TAZ, and interacts with TAZ through multiple domains including its carboxyl-terminal structure. Truncation mutants of TBX5 identified in patients with Holt-Oram syndrome were markedly impaired in their ability to associate with and be stimulated by TAZ. These findings reveal key roles for TAZ and YAP in the control of TBX5-dependent transcription and suggest the involvement of these coactivators in cardiac and limb development.transcriptional coactivator ͉ organ development ͉ hereditary birth defects T he activation of specific programs of gene expression during cell differentiation and organ development depends on combinatorial interactions among DNA-binding transcription factors, transcriptional cofactors, and histone-modifying enzymes (1, 2). Additional specificity and fine-tuning of gene expression is achieved by signal-dependent modulation of the expression and activity of the components of such multiprotein transcriptional complexes.Members of the T-box family of transcription factors regulate a variety of developmental processes in vertebrates and invertebrates, including specification of mesoderm, development of the heart, vasculature, and limbs and tumorigenesis (3-5). The T-box, which encodes a conserved 180-amino acid DNA-binding domain, has been identified in at least 18 mammalian T-box genes. In many cases, haploinsufficiency of T-box genes results in dramatic morphological abnormalities, emphasizing the importance of specific thresholds of transcriptional activity of T-box factors for developmental decisions (4). For example, heterozygous mutations in TBX1 have been implicated in 22q11 deletion (DiGeorge) syndrome, characterized by abnormalities in the aortic arch arteries due to defects in neural crest cell migration (4, 6), and mutations in TBX5 cause Holt-Oram syndrome (HOS), which manifests as a variety of cardiac and upper limb abnormalities (7-11).TBX5 is expressed in the embryonic heart and forelimbs and regulates transcription of downstream genes, such as those encoding atrial natriuretic factor (ANF) and fibroblast growth factor 10 (Fgf10) by binding to TBX-binding DNA elements (TBEs) (12-17). Targeted deletion of the Tbx5 gene in mice results in embryonic lethality with severe cardiac defects (13), and mice with limb-specific Tbx5 deletion show no ...

Molecular antagonism between X-chromosome and autosome signals determines nematode sex

“…For example, the T-box transcription factor TBX5 plays an essential, dose-dependent role in both cardiac and limb development (Mori and Bruneau 2004;Murakami et al 2005). As with sea-1, the TBX5 gene is haploinsufficient.…”

“…The findings that XSE-and ASE-binding sites are distinct and nonoverlapping and that SEX-1 and SEA-1 can bind simultaneously to the same DNA fragment suggest that direct competition for binding to xol-1 is not likely to underlie the antagonistic molecular interactions between these XSEs and ASEs at the xol-1 promoter. Instead, because nuclear receptors, ONECUT homeobox proteins, and T-box proteins repress or activate transcription by tethering corepressors or coactivators to their gene targets (Asahara et al 1999;Maira et al 2003;Privalsky 2004;Murakami et al 2005), an attractive alternative model is that XSEs and ASEs recruit cofactors with reciprocal enzymatic activities to the xol-1 promoter to elicit opposite transcriptional states. Common cofactors are those that modify histones to regulate transcription, including histone acetyltransferases and methyltransferases for gene activation and histone deacetylases for gene repression (Privalsky 2004;Lee et al 2005a,b).…”

“…The known XSE-and ASEbinding sites are distinct and nonoverlapping, suggesting that direct competition for binding to xol-1 is unlikely to be the mechanism by which XSEs oppose ASEs. Since other T-box proteins, nuclear receptors, and homeobox proteins tether coactivators or corepressors to specific binding sites (Asahara et al 1999;Privalsky 2004;Murakami et al 2005), the most plausible model is that XSEs and ASEs antagonize each other by recruiting cofactors with reciprocal activities that induce opposite transcriptional states. In summary, we demonstrated that multiple, antagonistic molecular interactions carried out on Figure 1.…”

Integrating developmental signals: a Hippo in the (path)way

“…Different isoforms of TAZ and YAP exist that possess either one or two WW domains, and this has been shown to provide differential activity (Komuro et al, 2003;Webb et al, 2011). Some of the TAZ/YAP nuclear DNA-binding partners that interact with the WW domain include RUNX1, RUNX2, p73, PAX3, PAX8, TTF-1 (also known as NKX2.1), TBX5 (also known as NKX2.5), PPARg and SMAD1 (Strano et al, 2001;Cui et al, 2003;Park et al, 2004;Murakami et al, 2005Murakami et al, , 2006Hong and Yaffe, 2006;Alarcon et al, 2009;Di Palma et al, 2009). TAZ/YAP possess additional domains that are important for transcription factor binding, including a coiled-coil domain that facilitates interactions with the TGFb-regulated SMADs (Varelas et al, 2008), and an N-terminal domain that binds to the TEAD family of transcription factors (Vassilev et al, 2001;Zhao et al, 2008).…”

The Hippo Tumor Pathway Promotes TAZ Degradation by Phosphorylating a Phosphodegron and Recruiting the SCFβ-TrCP E3 Ligase

“…TAZ, first identified as a 14-3-3-binding protein, shares ϳ50% sequence identity with YAP and has also been shown to function as a transcriptional co-activator downstream of the Hippo pathway (14,15). TAZ is involved in the development of multiple organs such as lung, fat, muscle, bone, limb, and heart as well as many cellular processes including stem cell differentiation, cell proliferation, epithelial mesenchymal transition (EMT) 4 (15)(16)(17)(18)(19)(20)(21). Taz knock-out mice develop two severe abnormalities: polycystic kidney disease and emphysema (22,23).…”