Homeobox protein TGIF1 explained

Homeobox protein TGIF1 is a protein that, in humans, is encoded by the TGIF1 gene.^{[1] [2] [3]} Alternative splicing has been observed at this locus and eight variants, encoding four distinct isoforms, are described.

Function

The protein encoded by this gene is a member of the three-amino acid loop extension (TALE) superclass of atypical homeodomains. TALE homeobox proteins are highly conserved transcription regulators. This particular homeodomain binds to a previously characterized retinoid X receptor responsive element from the cellular retinol-binding protein II promoter. In addition to its role in inhibiting 9-cis-retinoic acid-dependent RXR alpha transcription activation of the retinoic acid responsive element, the protein is an active transcriptional co-repressor of SMAD2 and may participate in the transmission of nuclear signals during development and in the adult.

Clinical significance

Mutations in this gene are associated with holoprosencephaly type 4, which is a structural anomaly of the brain. It has also been associated with risk of otitis media (inflammation of the middle ear)

Interactions

Homeobox protein TGIF1 has been shown to interact with:

• C-jun,^[4]
• CTBP1,
• HDAC1,^{[5] [6]} and
• Mothers against decapentaplegic homolog 2.^{[4] [7]}

Further reading

• El-Jaick KB, Powers SE, Bartholin L, Myers KR, Hahn J, Orioli IM, Ouspenskaia M, Lacbawan F, Roessler E, Wotton D, Muenke M . Functional analysis of mutations in TGIF associated with holoprosencephaly . Mol. Genet. Metab. . 90 . 1 . 97–111 . 2007 . 16962354 . 1820763 . 10.1016/j.ymgme.2006.07.011 .
• Münke M, Page DC, Brown LG, Armson BA, Zackai EH, Mennuti MT, Emanuel BS . Molecular detection of a Yp/18 translocation in a 45,X holoprosencephalic male . Hum. Genet. . 80 . 3 . 219–23 . 1989 . 3192211 . 10.1007/BF01790089 . 15442879 .
• Overhauser J, Mitchell HF, Zackai EH, Tick DB, Rojas K, Muenke M . Physical mapping of the holoprosencephaly critical region in 18p11.3 . Am. J. Hum. Genet. . 57 . 5 . 1080–5 . 1995 . 7485158 . 1801375 .
• Wotton D, Lo RS, Lee S, Massagué J . A Smad transcriptional corepressor . Cell . 97 . 1 . 29–39 . 1999 . 10199400 . 10.1016/S0092-8674(00)80712-6 . 6907878 . free .
• Yang Y, Hwang CK, D'Souza UM, Lee SH, Junn E, Mouradian MM . Three-amino acid extension loop homeodomain proteins Meis2 and TGIF differentially regulate transcription . J. Biol. Chem. . 275 . 27 . 20734–41 . 2000 . 10764806 . 10.1074/jbc.M908382199 . free .
• Melhuish TA, Wotton D . The interaction of the carboxyl terminus-binding protein with the Smad corepressor TGIF is disrupted by a holoprosencephaly mutation in TGIF . J. Biol. Chem. . 275 . 50 . 39762–6 . 2001 . 10995736 . 10.1074/jbc.C000416200 . free .
• Lo RS, Wotton D, Massagué J . Epidermal growth factor signaling via Ras controls the Smad transcriptional co-repressor TGIF . EMBO J. . 20 . 1–2 . 128–36 . 2001 . 11226163 . 140192 . 10.1093/emboj/20.1.128 .
• Pessah M, Prunier C, Marais J, Ferrand N, Mazars A, Lallemand F, Gauthier JM, Atfi A . c-Jun interacts with the corepressor TG-interacting factor (TGIF) to suppress Smad2 transcriptional activity . Proc. Natl. Acad. Sci. U.S.A. . 98 . 11 . 6198–203 . 2001 . 11371641 . 33445 . 10.1073/pnas.101579798 . 2001PNAS...98.6198P . free .
• Yu X, Li P, Roeder RG, Wang Z . Inhibition of androgen receptor-mediated transcription by amino-terminal enhancer of split . Mol. Cell. Biol. . 21 . 14 . 4614–25 . 2001 . 11416139 . 87125 . 10.1128/MCB.21.14.4614-4625.2001 .
• Wotton D, Knoepfler PS, Laherty CD, Eisenman RN, Massagué J . The Smad transcriptional corepressor TGIF recruits mSin3 . Cell Growth Differ. . 12 . 9 . 457–63 . 2001 . 11571228 .
• Sharma M, Sun Z . 5'TG3' interacting factor interacts with Sin3A and represses AR-mediated transcription . Mol. Endocrinol. . 15 . 11 . 1918–28 . 2002 . 10.1210/mend.15.11.0732 . 11682623 . free .
• Dintilhac A, Bernués J . HMGB1 interacts with many apparently unrelated proteins by recognizing short amino acid sequences . J. Biol. Chem. . 277 . 9 . 7021–8 . 2002 . 11748221 . 10.1074/jbc.M108417200 . free . 10261/112516 . free .
• Chen CP, Chern SR, Du SH, Wang W . Molecular diagnosis of a novel heterozygous 268C-->T (R90C) mutation in TGIF gene in a fetus with holoprosencephaly and premaxillary agenesis . Prenat. Diagn. . 22 . 1 . 5–7 . 2002 . 11810641 . 10.1002/pd.202 . 8297098 .
• Aguilella C, Dubourg C, Attia-Sobol J, Vigneron J, Blayau M, Pasquier L, Lazaro L, Odent S, David V . Molecular screening of the TGIF gene in holoprosencephaly: identification of two novel mutations . Hum. Genet. . 112 . 2 . 131–4 . 2003 . 12522553 . 10.1007/s00439-002-0862-8 . 2238304 .
• Chen F, Ogawa K, Nagarajan RP, Zhang M, Kuang C, Chen Y . Regulation of TG-interacting factor by transforming growth factor-beta . Biochem. J. . 371 . Pt 2 . 257–63 . 2003 . 12593671 . 1223316 . 10.1042/BJ20030095 .
• Lam DS, Lee WS, Leung YF, Tam PO, Fan DS, Fan BJ, Pang CP . TGFbeta-induced factor: a candidate gene for high myopia . Invest. Ophthalmol. Vis. Sci. . 44 . 3 . 1012–5 . 2003 . 12601022 . 10.1167/iovs.02-0058 .
• Dubourg C, Lazaro L, Pasquier L, Bendavid C, Blayau M, Le Duff F, Durou MR, Odent S, David V . Molecular screening of SHH, ZIC2, SIX3, and TGIF genes in patients with features of holoprosencephaly spectrum: Mutation review and genotype-phenotype correlations . Hum. Mutat. . 24 . 1 . 43–51 . 2004 . 15221788 . 10.1002/humu.20056 . 34076824 .

Notes and References

1. Bertolino E, Reimund B, Wildt-Perinic D, Clerc RG . A novel homeobox protein which recognizes a TGT core and functionally interferes with a retinoid-responsive motif . J Biol Chem . 270 . 52 . 31178–88 . February 1996 . 8537382 . 10.1074/jbc.270.52.31178 . free .
2. Gripp KW, Wotton D, Edwards MC, Roessler E, Ades L, Meinecke P, Richieri-Costa A, Zackai EH, Massagué J, Muenke M, Elledge SJ . Mutations in TGIF cause holoprosencephaly and link NODAL signalling to human neural axis determination . Nat Genet . 25 . 2 . 205–8 . June 2000 . 10835638 . 10.1038/76074 . 24723063 .
3. Web site: Entrez Gene: TGIF1 TGFB-induced factor homeobox 1.
4. Pessah M, Prunier C, Marais J, Ferrand N, Mazars A, Lallemand F, Gauthier JM, Atfi A . c-Jun interacts with the corepressor TG-interacting factor (TGIF) to suppress Smad2 transcriptional activity . Proc. Natl. Acad. Sci. U.S.A. . 98 . 11 . 6198–203 . May 2001 . 11371641 . 33445 . 10.1073/pnas.101579798 . 2001PNAS...98.6198P . free .
5. Melhuish TA, Wotton D . The interaction of the carboxyl terminus-binding protein with the Smad corepressor TGIF is disrupted by a holoprosencephaly mutation in TGIF . J. Biol. Chem. . 275 . 50 . 39762–6 . December 2000 . 10995736 . 10.1074/jbc.C000416200 . free .
6. Melhuish TA, Gallo CM, Wotton D . TGIF2 interacts with histone deacetylase 1 and represses transcription . J. Biol. Chem. . 276 . 34 . 32109–14 . August 2001 . 11427533 . 10.1074/jbc.M103377200 . free .
7. Wotton D, Lo RS, Lee S, Massagué J . A Smad transcriptional corepressor . Cell . 97 . 1 . 29–39 . April 1999 . 10199400 . 10.1016/s0092-8674(00)80712-6. 6907878 . free .