Hairy-related transcription factors inhibit GATA-dependent cardiac gene expression through a signal-responsive mechanism. J Biol Chem 2004 Dec 24;279(52):54937-43
Date
10/16/2004Pubmed ID
15485867DOI
10.1074/jbc.M409879200Scopus ID
2-s2.0-19944427762 (requires institutional sign-in at Scopus site) 62 CitationsAbstract
Combinatorial actions of transcription factors in multiprotein complexes dictate gene expression profiles in cardiac development and disease. The Hairy-related transcription factor (HRT) family of basic helix-loop-helix proteins is composed of transcriptional repressors highly expressed in the cardiovascular system. However, it has remained unclear whether HRT proteins modulate gene expression driven by cardiac transcriptional activators. Here, we have shown that HRT proteins inhibit cardiac gene transcription by interfering with GATA transcription factors that are implicated in cardiac development and hypertrophy. HRT proteins inhibited GATA-dependent transcriptional activation of cardiac gene promoters such as the atrial natriuretic factor (ANF) promoter. Adenovirus-mediated expression of Hrt2 suppressed mRNA expression of ANF and other cardiac-specific genes in cultured cardiomyocytes. Among various signaling molecules implicated in cardiomyocyte growth, constitutively active Akt1/protein kinase B alpha relieved Hrt2-mediated inhibition of GATA-dependent transcription. HRT proteins physically interacted with GATA proteins, and the basic domain of HRT was critical for physical association as well as transcriptional inhibition. These results suggest that HRT proteins may regulate specific sets of cardiac genes by modulating the function of GATA proteins and other cardiac transcriptional activators in a signal-dependent manner.
Author List
Kathiriya IS, King IN, Murakami M, Nakagawa M, Astle JM, Gardner KA, Gerard RD, Olson EN, Srivastava D, Nakagawa OMESH terms used to index this publication - Major topics in bold
AnimalsAtrial Natriuretic Factor
Basic Helix-Loop-Helix Transcription Factors
COS Cells
Cardiomegaly
Cells, Cultured
DNA-Binding Proteins
GATA4 Transcription Factor
Gene Deletion
Gene Expression
Helix-Loop-Helix Motifs
Humans
Luciferases
Mice
Myocytes, Cardiac
Promoter Regions, Genetic
Proto-Oncogene Proteins
Proto-Oncogene Proteins c-akt
RNA, Messenger
Rats
Recombinant Fusion Proteins
Repressor Proteins
Signal Transduction
Transcription Factors
Transfection
