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Novel homeobox gene, denoted TGIF (interacting factor), belongs to an expanding TALE (three amino acid loop extension) superclass of atypical homeodomains. The TGIF homeodomain binds to a previously characterized retinoid X receptor (RXR) responsive element from the cellular retinol-binding protein II promoter (CRBPII-RXRE), which contains an unusual DNA target for a homeobox (1). In vitro studies have implicated TGIF as a transcriptional repressor and corepressor in retinoid and TGF-beta signaling pathways that regulate several important biological processes. Heterozygous nonsense and missense mutations of the human TGIF gene have been associated with holoprosencephaly, the most common congenital malformation of the forebrain (2). It has been reported that TGIF plays an unexpected role in the inhibition of Smad2 phosphorylation, which occurs by a mechanism independent of its association with Smad2. This inhibitory function of TGIF is executed in concert with c-Jun, which facilitates the interaction of TGIF with cPML, resulting in the nuclear sequestration of cPML and the disruption of the cPML-SARA complex (3).
