MultistepRegulationofTranscriptionbyPitx2

Many transcription factors play essential roles in normal development by determining the proliferation and differentiation of cells. The coordinated transcriptional control of proliferation in specific developmental cell types is crucial in multiple developmental settings. One of a family of three bicoid-related transcription factors, Pitx2 acts downstream of the extracellular signaling protein Wnt to drive proliferation of cells with specific developmental fates, including cells in the pituitary, cardiac outflow region, and muscle. Wnt binds to Frizzled, a G-protein coupled receptor, activating homologs of the Drosophila Disheveled protein. Activation of Frizzled and Disheveled inhibits the kinase GSK-3 beta, part of a protein complex in the absence of Wnt signaling, causing beta-catenin protein to accumulate in the cytoplasm. Beta-catenin is known to alter the function of transcription factors like TCF/Lef. One result of Wnt signaling is activation of the transcription factor Lef by beta-catenin, inducing Pitx2 expression. Wnt activation also changes Pitx2 from a repressor to an activator by causing transcriptional corepressors like histone deacetylase 1 (HDAC1) bound to Pitx2 to be exchanged for coactivators. With coactivators bound, Pitx2 activates transcription of genes that regulate the cell cycle like Cyclin D2. Different coactivators are recruited by Pitx2 and other transcription factors like Myc to the Cyclin D2 promoter, with CBP/p300 recruited first, followed by NLI/Ldb/CLIM, Tip60/TRRAP, and PBP coactivators. Many of these coactivators help to alter histone acetylation and chromatin structure as part of transcriptional activation. The activation of cell cycle genes by Pitx2 ultimately stimulates the proliferation of specific cell types with the confluence of tissue-specific gene expression, growth factor signaling and coactivator recruitment.

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