Cyclin D2 is a GATA4 cofactor in cardiogenesis.
The G1 cyclins play a pivotal role in regulation of cell differentiation and proliferation. The mechanisms underlying their cell-specific roles are incompletely understood. Here, we show that a G1 cyclin, cyclin D2 (CycD2), enhances the activity of transcription factor GATA4, a key regulator of cardiomyocyte growth and differentiation. GATA4 recruits CycD2 to its target promoters, and their interaction results in synergistic activation of GATA-dependent transcription. This effect is specific to CycD2 because CycD1 is unable to potentiate activity of GATA4 and is CDK-independent. GATA4 physically interacts with CycD2 through a discreet N-terminal activation domain that is essential for the cardiogenic activity of GATA4. Human mutations in this domain that are linked to congenital heart disease interfere with CycD2-GATA4 synergy. Cardiogenesis assays in Xenopus embryos indicate that CycD2 enhances the cardiogenic function of GATA4. Together, our data uncover a role for CycD2 as a cardiogenic coactivator of GATA4 and suggest a paradigm for cell-specific effects of cyclin Ds.
Laboratory of Cardiac Development and Differentiation, Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, ON, Canada, K1N 6N5.
Abir
A
Yamak
Branko V
BV
Latinkic
Rola
R
Dali
Rana
R
Temsah
Mona
M
Nemer
D000595:Amino Acid Sequence; D000818:Animals; D056742:Cyclin D2 / Q000737:chemistry / Q000502:physiology*; D050991:GATA4 Transcription Factor / Q000502:physiology*; D006321:Heart / Q000196:embryology*; D006801:Humans; D008969:Molecular Sequence Data; D038081:Organogenesis / Q000502:physiology*; D017386:Sequence Homology, Amino Acid; D015534:Trans-Activators / Q000502:physiology
D056742:Cyclin D2; D050991:GATA4 Transcription Factor; C484170:GATA4 protein, human; D015534:Trans-Activators
GATA transcription factors; heart development; heart repair