The Interaction of the Carboxyl Terminus-binding Protein with the Smad Corepressor TGIF Is Disrupted by a Holoprosencephaly Mutation in TGIF

Melhuish, Tiffany A.; Wotton, David

doi:10.1074/jbc.c000416200

Cited by 96 publications

(90 citation statements)

References 55 publications

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“…Recently, TGIF was shown to recruit mSin3 to the TGF-b-activated Smad complex (Wotton et al, 1999b;. The TGIF interacting co-repressor, C-terminal binding protein (CtBP), can enhance the inactivating effect of TGIF on TGF-b-induced transcriptional responses (Melhuish and Wotton, 2000). In addition, binding of TGIF to Smads occurs via the C-terminal domain and is mutually exclusive with p300/CBP interaction, and will lead to inactivation of gene expression (Fig.…”

Section: Transcriptional Co-activators and Co-repressors Of Smadsmentioning

confidence: 99%

Regulation of cell proliferation by Smad proteins

Dijke

Goumans

Itoh

2002

Journal Cellular Physiology

398

278

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Transforming growth factor-b (TGF-b) family members which include TGF-bs, activins, and bone morphogenetic proteins (BMPs) regulate a broad spectrum of biological responses on a large variety of cell types. TGF-b family members initiate their cellular responses by binding to distinct receptors with intrinsic serine/ threonine kinase activity and activation of speci®c downstream intracellular effectors termed Smad proteins. Smads relay the signal from the cell membrane to the nucleus, where they affect the transcription of target genes. Smad activation, subcellular distribution, and stability have been found to be intricately regulated and a broad array of transcription factors have been identi®ed as Smad partners. Important activities of TGF-b are its potent anti-mitogenic and pro-apoptotic effects that, at least in part, are mediated via Smad proteins. Escape from TGF-b/ Smad-induced growth inhibition and apoptosis is frequently observed in tumors. Certain Smads have been found to be mutated in speci®c types of cancer and gene ablation of particular Smads in mice has revealed increased rate of tumorigenesis. In late stage tumors, TGF-b has been shown to function as a tumor promoter. TGFb can stimulate the de-differentiation of epithelial cells to malignant invasive and metastatic ®broblastic cells. Interestingly, TGF-b may mediate these effects directly on tumor cells via subverted Smad-dependent and/or Smad-independent pathways.

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Section: Transcriptional Co-activators and Co-repressors Of Smadsmentioning

confidence: 99%

Regulation of cell proliferation by Smad proteins

Dijke

Goumans

Itoh

2002

Journal Cellular Physiology

398

278

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“…In the first mutation, an 83C3 G base substitution is predicted to cause a S28C amino acid change (Gripp et al, 2000). The resultant mutant was found to lack CtBP binding activity and was somewhat compromised in its ability to repress TGF-␤-mediated gene expression (Melhuish and Wotton, 2000). The second mutation (188C3 G) is predicted to cause a P63R change.…”

Section: A Tgif Mutation Identified In An Hpe Patient Alters the Actimentioning

confidence: 99%

TGIF, a gene associated with human brain defects, regulates neuronal development

2006

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-TG-3 -interacting factor (TGIF) is an atypical homeodomain protein.In vitro studies have shown that TGIF can repress transcription mediated by either of two signaling pathways: TGF-␤ and retinoic acid signaling. Mutations in TGIF have been detected in patients with holoprosencephaly (HPE), a severe brain malformation associated with mental retardation. Thus, TGIF must play an essential role in nervous system development. However, the precise function of TGIF during vertebrate neural development is unknown. To investigate the in vivo role of TGIF, we overexpressed TGIF in the developing chick neural tube. Overexpressed TGIF decreased expression of specific genes expressed in dorsally restricted domains of the neural tube, including Cath1, Msx2, Pax6, and Wnt1. In contrast, the expression of other transcription factors, including those necessary for ventral fate such as Nkx2.2, was not affected. Furthermore, a missense mutation in TGIF identified in an HPE patient disrupted the activity of TGIF. In addition, the related protein TGIF2 did not demonstrate the same activity as TGIF. Our data suggest that TGIF plays an important role in regulating the expression of genes expressed in specific dorsal-ventral domains during neural development.

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“…TGIF interacts with a TGF-β activated Smad complex to repress Smad-mediated transcription, this repression involves the recruitment of CtBPs by a PxDLS motif in TGIF. 85 The importance of the TGIF-CtBP interaction in human development is demonstrated by an inherited point mutation in the PxDLS motif in TGIF, which results in defects in craniofacial development. 85 CtBPs also interact with the inhibitory Smad, Smad6, which contributes to the repression of Id-1 gene transcription.…”

Section: Transforming Growth Factor-β (Tgf-β) Signaling Pathwaysmentioning

confidence: 99%