Negative regulation of selected bHLH proteins by eHAND.
The bHLH protein eHAND plays an important role in the development of extraembryonic, mesodermal, and cardiac cell lineages, presumably through heterodimerization with other HLH proteins and DNA binding. In this study, we have identified a novel transcriptional activity of eHAND. In transient transfection assays, eHAND is a potent inhibitor of activation by some but not all bHLH proteins. eHAND can prevent E-box DNA binding by these bHLH proteins. Interestingly, eHAND can also strongly inhibit transactivation activity by a MyoD approximately E47 tethered dimer, which suggests a distinct mechanism of action. eHAND also inhibits MyoD-dependent skeletal muscle cell differentiation and expression of the muscle-specific myosin heavy chain protein. In addition, we show that eHAND can repress activity of the natural p75LNGFR promoter, whose expression overlaps that of eHAND and dHAND. The inhibitory activity of eHAND may be attributed to multiple mechanisms, such as the ability to act as a corepressor, the presence of a repression domain, and its ability to sequester E proteins in an inactive complex. Based upon its inhibitory effect on bHLH proteins and cellular differentiation, we propose that eHAND may function by several mechanisms to promote placental giant cell proliferation by negatively regulating the activities of the bHLH protein MASH-2.
Bounpheng
M A
MA
Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, Texas, 78245-3207, USA.
Morrish
T A
TA
Dodds
S G
SG
Christy
B A
BA
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D001665:Binding Sites; D002454:Cell Differentiation; D002460:Cell Line; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D019281:Dimerization; D018257:Helix-Loop-Helix Motifs; D051379:Mice; D009132:Muscles / Q000166:cytology; D017570:MyoD Protein / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D020800:Receptor, Nerve Growth Factor / Q000235:genetics; D020218:Response Elements; D051820:TCF Transcription Factors; D058125:Transcription Factor 7-Like 1 Protein; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation
D051792:Basic Helix-Loop-Helix Proteins; D004247:DNA; D004268:DNA-Binding Proteins; D017570:MyoD Protein; D020800:Receptor, Nerve Growth Factor; D051820:TCF Transcription Factors; D058125:Transcription Factor 7-Like 1 Protein; D014157:Transcription Factors; C499317:Ascl1 protein, mouse; C489311:Ascl2 protein, mouse; C095572:Hand1 protein, mouse; C544912:TCF7L1 protein, human; C489532:Tcf12 protein, mouse; C544913:Tcf7l1 protein, mouse; C097341:helix-loop-helix protein, eHAND; C073366:TCF12 protein, human