Disease relevance of TGIF1

• Mutations in TGIF have been detected in patients with holoprosencephaly (HPE), a severe brain malformation associated with mental retardation [1].
• Haploinsufficient mutations in the TG-interacting factor (TGIF) gene were previously identified in a subset of HPE families and sporadic patients, and this gene is located within a region of chromosome 18 that is associated with nonrandom chromosomal aberrations in HPE patients [2].

High impact information on TGIF1

• We identified the homeodomain protein TGIF as a Smad2-binding protein and a repressor of transcription [3].
• A TGFbeta-activated Smad complex can recruit TGIF and histone deacetylases (HDACs) to a Smad target promoter, repressing transcription [3].
• Thus, upon entering the nucleus, a Smad2-Smad4 complex may interact with coactivators, forming a transcriptional activation complex, or with TGIF and HDACs, forming a transcriptional repressor complex [3].
• Furthermore, c-Jun(-/-) fibroblasts exhibit enhanced association of cPML with SARA. c-Jun(-/-) fibroblasts also lose their sensitivity to TGIF-mediated disruption of the cPML-SARA complex and of nuclear sequestration of cPML [4].
• In this study, we report an unexpected role of TGIF in the inhibition of Smad2 phosphorylation, which occurs by a mechanism independent of its association with Smad2 [4].

Biological context of TGIF1

• After transforming growth factorbeta (TGFbeta) stimulation, Smad proteins enter the nucleus and form transcriptional activation complexes or interact with TGIF, which functions as a corepressor [5].
• Furthermore, a missense mutation in TGIF identified in an HPE patient disrupted the activity of TGIF [1].
• The canonical binding site of TGIF is conserved and is an integral part of several responsive elements which are organized like the CRBPII-RXRE [6].
• Transient cellular transfections demonstrate that TGIF inhibits the 9-cis-retinoic acid-dependent RXR alpha transcription activation of the retinoic acid responsive element [6].
• This groups TGIF together with two other genes producing similar phenotypes, always early and cookie monster, as components of the machinery required for the activation of the spermatogenic programme of transcription [7].

Anatomical context of TGIF1

• Moreover, resistance to transforming growth factor beta (TGFbeta)-induced growth inhibition was enhanced in four cell lines with amplification and expression of TGIF, which encodes the repressor for TGFbeta-activated transcription, appears to be involved in the progression of ESC [8].
• By immunolabelling in mouse testes we show that TGIF is expressed in the early stages of spermatogenesis consistent with a conserved role in the activation of the spermatogenesis transcription programme [7].
• In order to map the putative HPE gene located on 18p (HPE4) more precisely, six patients with various cytogenetic 18p deletions and clinical features of HPE have been characterized by using a combination of somatic cell hybrid analysis and FISH [9].

Associations of TGIF1 with chemical compounds

• In vitro studies have shown that TGIF can repress transcription mediated by either of two signaling pathways: TGF-beta and retinoic acid signaling [1].
• For example, in the D(1A) gene, which encodes the predominant dopamine receptor in the striatum, Meis2 and TGIF bind to the activator sequence ACT (-1174 to -1154) and regulate transcription differentially in a cell type-specific manner [10].
• TGIF is a DNA-binding homeodomain protein that has been demonstrated to play a role in transforming growth factor beta-regulated transcription and implicated in the control of retinoid-responsive transcription [11].

Regulatory relationships of TGIF1

• The homeodomain protein TG-interacting factor (TGIF) represses transcription by histone deacetylase-dependent and -independent means [5].

Other interactions of TGIF1

• Among these patients, a deletion in the homeodomain of SIX3 and several polymorphisms in SIX3 and TGIF were identified [12].
• Heterozygous mutations in human TGIF result in holoprosencephaly, a severe genetic disorder affecting craniofacial development, suggesting that TGIF is critical for normal development [5].
• These include Patched (Ptc), Smoothened (Smo), cubitus interuptus (ci)/Gli, wingless (wg/Wnt, decapentaplegic (dpp)/BMP, Hedgehog interacting protein (Hip), nodal, Smads, One-eyed pinhead (Oep), and TG-Interacting Factor (TGIF) [13].
• Taken together, these results suggest that YES1, TYMS, HEC and TGIF are likely to be candidate targets for 18p11.3 amplification and be associated with esophageal tumorigenesis [8].
• Only four known genes, YES1, TYMS, HEC and TGIF showed amplification and consequent over-expression [8].

Analytical, diagnostic and therapeutic context of TGIF1

• TGIF: tracheal gas insufflation: for whom [14]?

References