A WW domain protein TAZ is a critical coactivator for TBX5, a transcription factor implicated in Holt-Oram syndrome.
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.
Murakami
Masao
M
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, 75390-9148, USA.
Nakagawa
Masayo
M
Olson
Eric N
EN
Nakagawa
Osamu
O
D000015:Abnormalities, Multiple / Q000235:genetics*; D000217:Acyltransferases; D000818:Animals; D015153:Blotting, Western; D017931:DNA Primers; D024202:Electrophoretic Mobility Shift Assay; D006330:Heart Defects, Congenital / Q000235:genetics*; D051548:Histone Acetyltransferases; D006801:Humans; D008156:Luciferases; D051379:Mice; D010957:Plasmids / Q000235:genetics; D011506:Proteins / Q000378:metabolism*; D034622:RNA Interference; D013577:Syndrome; D020825:T-Box Domain Proteins / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D015533:Transcriptional Activation / Q000235:genetics*
D017931:DNA Primers; D011506:Proteins; D020825:T-Box Domain Proteins; C103172:T-box transcription factor 5; D014157:Transcription Factors; D008156:Luciferases; D000217:Acyltransferases; C108675:TAFAZZIN protein, human; D051548:Histone Acetyltransferases