The basic-helix-loop-helix transcription factor HAND2 directly regulates transcription of the atrial naturetic peptide gene.
The HAND basic Helix-Loop-Helix (bHLH) transcription factors are essential for the development of heart and extra embryonic structures. Although essential for embryonic development, the molecular pathways in which HAND factors participate are poorly understood. In efforts to identify downstream transcriptional targets, we have determined that HAND2 regulates the transcription of the Atrial Naturetic Peptide (ANP) gene. Results show that ANP expression is reduced in HAND2 null mice. Transactivation assays show significant transcriptional upregulation of ANP by HAND2 and cotransfection experiments using HAND2 and E12 suggest that an E-protein/HAND heterodimer is the likely trans -acting complex. The required cis -elements reside within a 258bp proximal region that contains three evolutionarily conserved Ebox consensus sites. Surprisingly, mutations in these three sites suggest HAND2 activity is DNA-binding independent. In addition, HAND2 and the homeobox factor Nkx2.5 exhibit transcriptional synergy in the regulation of ANP. Taken together, this data shows that HAND2 is an upstream transcriptional regulator of ANP expression, and furthermore HAND2 can synergistically interact with Nkx2.5, showing a functional relationship between HAND2 and Nkx2.5 supporting the genetic observation, that mice null for both HAND2 and Nkx2.5 lack ventricle specification.
Thattaliyath
Bijoy D
BD
Department of Physiology, Mail Code-7756, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900, USA.
Firulli
Beth A
BA
Firulli
Anthony B
AB
D000818:Animals; D009320:Atrial Natriuretic Factor / Q000235:genetics*; D001483:Base Sequence; D051792:Basic Helix-Loop-Helix Proteins; D002460:Cell Line; D017124:Conserved Sequence; D004268:DNA-Binding Proteins / Q000378:metabolism; D017353:Gene Deletion; D005786:Gene Expression Regulation; D018257:Helix-Loop-Helix Motifs; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D017403:In Situ Hybridization; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012689:Sequence Homology, Nucleic Acid; D014157:Transcription Factors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000235:genetics*; D029867:Xenopus Proteins / Q000378:metabolism; D029961:Zebrafish Proteins
D009320:Atrial Natriuretic Factor; D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; D029867:Xenopus Proteins; D029961:Zebrafish Proteins; C498765:HAND2 protein, human; C095572:Hand1 protein, mouse; C498766:Hand2 protein, mouse; C095552:NKX2-5 protein, human; C484469:Nkx2-5 protein, mouse; C410915:hand2 protein, zebrafish; C097341:helix-loop-helix protein, eHAND