Physical and functional interaction between GATA-3 and Smad3 allows TGF-beta regulation of GATA target genes.
BACKGROUND
Members of the GATA family of zinc finger transcription factors are genetically controlled "master" regulators of development in the hematopoietic and nervous systems. Whether GATA factors also serve to integrate epigenetic signals on target promoters is, however, unknown. The transforming growth factor-beta (TGF-beta) superfamily is a large group of phylogenetically conserved secreted factors controlling cell proliferation, differentiation, migration, and survival in multiple tissues.


RESULTS
GATA-3, a key regulator of T helper cell development, was found to directly interact with Smad3, an intracellular signal transducer of TGF-beta. Complex formation required a central region in GATA-3 and the N-terminal domain of Smad3. GATA-3 mediated recruitment of Smad3 to GATA binding sites independently of Smad3 binding to DNA, and the two factors cooperated synergistically to regulate transcription from the IL-5 promoter in a TGF-beta-dependent manner. Treatment of T helper cells with TGF-beta promoted the formation of an endogenous Smad3/GATA-3 nuclear complex and stimulated production of the Th2 cytokine IL-10 in a Smad3- and GATA-3-dependent manner.


CONCLUSIONS
Although Smad proteins are known to interact with a number of general transcription factors, these are insufficient to explain the tissue-specific biology of TGF-beta proteins. Through its interaction with Smad3, GATA-3 is able to integrate a genetic program of cell differentiation with an extracellular signal, providing a molecular framework for the effects of TGF-beta on the development and function of specific subsets of immune cells and possibly other cell types.
Blokzijl
Andries
A
Division of Molecular Neurobiology, Department of Neuroscience, Karolinska Institute, 171 77, Stockholm, Sweden.
ten Dijke
Peter
P
Ibáñez
Carlos F
CF
D000818:Animals; D001665:Binding Sites; D019556:COS Cells; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology*; D050990:GATA3 Transcription Factor; D017930:Genes, Reporter; D006801:Humans; D016753:Interleukin-10 / Q000096:biosynthesis; D015848:Interleukin-5 / Q000235:genetics; D019169:Jurkat Cells; D046911:Macromolecular Substances; D011401:Promoter Regions, Genetic; D017434:Protein Structure, Tertiary; D051900:Smad3 Protein; D013601:T-Lymphocytes / Q000276:immunology; D015534:Trans-Activators / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology*; D015533:Transcriptional Activation; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
D004268:DNA-Binding Proteins; D050990:GATA3 Transcription Factor; C494749:GATA3 protein, human; D015848:Interleukin-5; D046911:Macromolecular Substances; C497790:SMAD3 protein, human; D051900:Smad3 Protein; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D016753:Interleukin-10