GATA-4 and MEF2C transcription factors control the tissue-specific expression of the alphaT-catenin gene CTNNA3.
AlphaT-catenin is a recently identified member of the alpha-catenin family of cell-cell adhesion molecules. Its expression is restricted mainly to cardiomyocytes, although it is also expressed in skeletal muscle, testis and brain. Like other alpha-catenins, alphaT-catenin provides an indispensable link between a cadherin-based adhesion complex and the actin cytoskeleton, resulting in strong cell-cell adhesion. We show here that the tissue-specificity of alphaT-catenin expression is controlled by its promoter region. By in silico analysis, we found that the alphaT-catenin promoter contains several binding sites for cardiac and muscle-specific transcription factors. By co-transfection studies in P19 embryonal carcinoma cells, we demonstrated that MEF2C and GATA-4 each have an activating effect on the alphaT-catenin promoter. Transfections with wild-type and mutant promoter constructs in cardiac HL-1 cells indicated that one GATA box is absolutely required for high alphaT-catenin promoter activity in these cells. Furthermore, we showed that the GATA-4 transcription factor specifically binds and activates the alphaT-catenin promoter in vivo in cardiac HL-1 cells. In vivo promoter analysis in transgenic mice revealed that the isolated alphaT-catenin promoter region could direct the tissue-specific expression of a LacZ reporter gene in concordance with endogenous alphaT-catenin expression.
Unit of Molecular and Cellular Oncology, Department for Molecular Biomedical Research, VIB-Ghent University, B-9052 Ghent-Zwijnaarde, Belgium.
Griet
G
Vanpoucke
Steven
S
Goossens
Bram
B
De Craene
Barbara
B
Gilbert
Frans
F
van Roy
Geert
G
Berx
D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002460:Cell Line; D003598:Cytoskeletal Proteins / Q000096:biosynthesis / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000502:physiology*; D050991:GATA4 Transcription Factor; D006801:Humans; D026161:MADS Domain Proteins; D064326:MEF2 Transcription Factors; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D032383:Myocytes, Cardiac / Q000378:metabolism; D018006:Myogenic Regulatory Factors / Q000502:physiology*; D009928:Organ Specificity; D011401:Promoter Regions, Genetic; D012045:Regulatory Sequences, Nucleic Acid; D016415:Sequence Alignment; D014157:Transcription Factors / Q000502:physiology*; D015533:Transcriptional Activation; D051178:alpha Catenin
C441963:CTNNA3 protein, human; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D050991:GATA4 Transcription Factor; D026161:MADS Domain Proteins; D064326:MEF2 Transcription Factors; C578040:MEF2C protein, human; C578041:Mef2c protein, mouse; D018006:Myogenic Regulatory Factors; D014157:Transcription Factors; D051178:alpha Catenin