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PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
1
pubmed:dateCreated
2003-9-26
pubmed:abstractText
Noradrenergic neuronal identity and differentiation are controlled by cascades of transcription factors acting downstream of BMP4, including the basic helix-loop-helix DNA binding protein HAND2 and the homeodomain factor Phox2a. Dopamine-beta-hydroxylase (DBH) is the penultimate enzyme required for synthesis of norepinephrine and is thus a noradrenergic cell type-specific marker. We have examined the interaction of HAND2 and Phox2a at the DBH promoter. Using transient transfection of P19 or NT-2 cells, HAND2 is shown to synergistically enhance Phox2a-driven transcriptional activity at the DBH promoter, an effect that is enhanced by cAMP. While mutation of the Phox2a homeodomain binding sites HD1, HD2, and HD3 results in the loss of HAND2/Phox2a transactivation of DBH, it is the interaction of HAND2/Phox2a at the CRE/AP1-HD1/2 domains in the DBH enhancer that are required for synergistic activation by HAND2. We find that HAND2 functions as a transcriptional activator without directly binding to E-box sequences in the DBH promoter, suggesting that HAND2-mediated DBH activity occurs by protein-protein interactions with other transcriptional regulators. Although we were unable to detect interaction of HAND2 and Phox2a in IP/Western blots, HAND2 synergistic activation of DBH is blocked by E1A, suggesting that HAND2 interacts with CBP (cAMP response element binding protein) in this transcriptional complex. In the presence of the putative HAND2 dimerization partner, E12, synergistic activation of DBH transcription is titrated away, suggesting that HAND2 does not functionally dimerize with E12 in the DBH transcription complex. Our data suggest that HAND2 regulates cell type-specific expression of norepinephrine in concert with Phox2a by a novel mechanism.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
http://linkedlifedata.com/resource/pubmed/chemical/Basic Helix-Loop-Helix..., http://linkedlifedata.com/resource/pubmed/chemical/Cyclic AMP, http://linkedlifedata.com/resource/pubmed/chemical/DNA, http://linkedlifedata.com/resource/pubmed/chemical/Dopamine beta-Hydroxylase, http://linkedlifedata.com/resource/pubmed/chemical/HAND2 protein, human, http://linkedlifedata.com/resource/pubmed/chemical/Homeodomain Proteins, http://linkedlifedata.com/resource/pubmed/chemical/Nerve Tissue Proteins, http://linkedlifedata.com/resource/pubmed/chemical/Nuclear Proteins, http://linkedlifedata.com/resource/pubmed/chemical/PHOX2A protein, human, http://linkedlifedata.com/resource/pubmed/chemical/Trans-Activators, http://linkedlifedata.com/resource/pubmed/chemical/Transcription Factors, http://linkedlifedata.com/resource/pubmed/chemical/Zebrafish Proteins, http://linkedlifedata.com/resource/pubmed/chemical/hand2 protein, zebrafish
pubmed:status
MEDLINE
pubmed:month
Oct
pubmed:issn
0012-1606
pubmed:author
pubmed:issnType
Print
pubmed:day
1
pubmed:volume
262
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
183-93
pubmed:dateRevised
2011-9-22
pubmed:meshHeading
pubmed:year
2003
pubmed:articleTitle
HAND2 synergistically enhances transcription of dopamine-beta-hydroxylase in the presence of Phox2a.
pubmed:affiliation
Department of Anatomy and Neurobiology, Medical College of Ohio, 3000 Arlington Ave., Toledo, OH 43614, USA.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, Non-U.S. Gov't