Post-Transcriptional Regulation of PARP7 Protein Stability Is Controlled by Androgen Signaling.

Poly-ADP-ribose polymerases (PARPs) are enzymes that catalyze ADP-ribosylation and play critical roles in normal and disease settings. The PARP family member, PARP7, is a mono-ADP-ribosyltransferase that has been suggested to play a tumor suppressive role in breast, ovarian, and colorectal cancer. Here, we have investigated how androgen signaling regulates PARP7 homeostasis in prostate cancer cells, where is a direct target gene of AR.

TGIF transcription factors repress acetyl CoA metabolic gene expression and promote intestinal tumor growth.

Tgif1 (thymine-guanine-interacting factor 1) and Tgif2 repress gene expression by binding directly to DNA or interacting with transforming growth factor (TGF) β-responsive SMADs. Tgifs are essential for embryogenesis and may function in tumor progression. By analyzing both gain and loss of Tgif function in a well-established mouse model of intestinal cancer, we show that Tgifs promote adenoma growth in the context of mutant ().

Myt1 and Myt1l transcription factors limit proliferation in GBM cells by repressing YAP1 expression.

Myelin transcription factor 1 (Myt1) and Myt1l (Myt1-like) are zinc finger transcription factors that regulate neuronal differentiation. Reduced Myt1l expression has been implicated in glioblastoma (GBM), and the related St18 was originally identified as a potential tumor suppressor for breast cancer. We previously analyzed changes in gene expression in a human GBM cell line with re-expression of either Myt1 or Myt1l.

Overexpression of transforming growth factor β induced factor homeobox 1 represses NPC1L1 and lowers markers of intestinal cholesterol absorption.

Background And Aims: Transforming growth factor β induced factor homeobox 1 (TGIF1) is a transcriptional repressor that limits the response to transforming growth factor ß signaling and also represses transcription independent of this pathway. Recently, we found higher serum cholesterol levels and more hepatic lipid accumulation in mice lacking Tgif1, and showed that TGIF1 can repress the expression of Soat2, the gene encoding the cholesterol esterifying enzyme acyl-Coenzyme A:cholesterol acyltransferase 2. Although there is evidence that TGIF1 plays a role in lipid metabolism, its role in this metabolic pathway is not fully characterized.

TGFβ signaling limits lineage plasticity in prostate cancer.

Although treatment options for localized prostate cancer (CaP) are initially effective, the five-year survival for metastatic CaP is below 30%. Mutation or deletion of the PTEN tumor suppressor is a frequent event in metastatic CaP, and inactivation of the transforming growth factor (TGF) ß signaling pathway is associated with more advanced disease. We previously demonstrated that mouse models of CaP based on inactivation of Pten and the TGFß type II receptor (Tgfbr2) rapidly become invasive and metastatic.

Analysis of transcriptional activity by the Myt1 and Myt1l transcription factors.

Myt1 and Myt1l (Myelin transcription factor 1, and Myt1-like) are members of a small family of closely related zinc finger transcription factors, characterized by two clusters of C2HC zinc fingers. Both are widely expressed during early embryogenesis, but are largely restricted to expression within the brain in the adult. Myt1l, as part of a three transcription factor mix, can reprogram fibroblasts to neurons and plays a role in maintaining neuronal identity.

The protein kinase C super-family member PKN is regulated by mTOR and influences differentiation during prostate cancer progression.

Background: Phosphoinositide-3 (PI-3) kinase signaling has a pervasive role in cancer. One of the key effectors of PI-3 kinase signaling is AKT, a kinase that promotes growth and survival in a variety of cancers. Genetically engineered mouse models of prostate cancer have shown that AKT signaling is sufficient to induce prostatic epithelial neoplasia (PIN), but insufficient for progression to adenocarcinoma.

Tgif1 and Tgif2 Repress Expression of the RabGAP Evi5l.

Mouse embryos conditionally lacking Tgif1 and Tgif2 have holoprosencephaly and defects in left-right asymmetry. To identify pathways affected by loss of Tgif function during embryogenesis, we performed transcriptome profiling on whole mouse embryos. Among the genes with altered expression in embryos lacking Tgifs were a number with links to cilium function.

Genetic and Molecular Analyses indicate independent effects of TGIFs on Nodal and Gli3 in neural tube patterning.

Holoprosencephaly (HPE) is a prevalent craniofacial developmental disorder that has both genetic and environmental causes. The gene encoding TG-interacting factor 1 (TGIF1) is among those that are routinely screened in HPE patients. However, the mechanisms by which TGIF1 variants cause HPE are not fully understood.

Tgif1 and Tgif2 Regulate Axial Patterning in Mouse.

Tgif1 and Tgif2 are transcriptional repressors that inhibit the transcriptional response to transforming growth factor β signaling, and can repress gene expression by direct binding to DNA. Loss of function mutations in TGIF1 are associated with holoprosencephaly (HPE) in humans. In mice, embryos lacking both Tgif1 and Tgif2 fail to complete gastrulation, and conditional double null embryos that survive past gastrulation have HPE and do not survive past mid-gestation.

Prostate cancer induced by loss of Apc is restrained by TGFβ signaling.

Recent work with mouse models of prostate cancer (CaP) has shown that inactivation of TGFβ signaling in prostate epithelium can cooperate with deletion of the Pten tumor suppressor to drive locally aggressive cancer and metastatic disease. Here, we show that inactivating the TGFβ pathway by deleting the gene encoding the TGFβ type II receptor (Tgfbr2) in combination with a deletion of the Apc tumor suppressor gene specifically in mouse prostate epithelium, results in the rapid onset of invasive CaP. Micro-metastases were observed in the lymph nodes and lungs of a proportion of the double mutant mice, whereas no metastases were observed in Apc single mutant mice.

TG-interacting factor 1 acts as a transcriptional repressor of sterol O-acyltransferase 2.

Acat2 [gene name: sterol O-acyltransferase 2 (SOAT2)] esterifies cholesterol in enterocytes and hepatocytes. This study aims to identify repressor elements in the human SOAT2 promoter and evaluate their in vivo relevance. We identified TG-interacting factor 1 (Tgif1) to function as an important repressor of SOAT2.

Premature senescence and increased TGFβ signaling in the absence of Tgif1.

Transforming growth factor β (TGFβ) signaling regulates cell cycle progression in several cell types, primarily by inducing a G1 cell cycle arrest. Tgif1 is a transcriptional corepressor that limits TGFβ responsive gene expression. Here we demonstrate that primary mouse embryo fibroblasts (MEFs) lacking Tgif1 proliferate slowly, accumulate increased levels of DNA damage, and senesce prematurely.

Tgif1 represses apolipoprotein gene expression in liver.

TG-interacting factor (Tgif1) represses gene expression by interaction with general corepressors, and can be recruited to target genes by transforming growth factor beta (TGFβ) activated Smads, or by the retinoid X receptor (RXR). Here we show that Tgif1 interacts with the LXRα nuclear receptor and can repress transcription from a synthetic reporter activated by LXRα. In cultured cells reducing endogenous Tgif1 levels resulted in increased expression of LXRα target genes.

Inhibition of CtBP1 activity by Akt-mediated phosphorylation.

Pc2 (Cbx4) is a member of the chromobox family of polycomb proteins, and is a SUMO E3 ligase for the transcriptional corepressor CtBP1. Here, we show that both CtBP1 and Pc2 are phosphorylated by the kinase Akt1, which is activated by growth factor signaling via the PI3-kinase pathway. In the presence of Pc2, phosphorylation of CtBP1 is increased, and this requires interaction of both CtBP1 and Akt1 with Pc2.

A role for non-covalent SUMO interaction motifs in Pc2/CBX4 E3 activity.

Background: Modification of proteins by the small ubiquitin like modifier (SUMO) is an essential process in mammalian cells. SUMO is covalently attached to lysines in target proteins via an enzymatic cascade which consists of E1 and E2, SUMO activating and conjugating enzymes. There is also a variable requirement for non-enzymatic E3 adapter like proteins, which can increase the efficiency and specificity of the sumoylation process.

Tgif1 and Tgif2 regulate Nodal signaling and are required for gastrulation.

Tgif1 and Tgif2 are transcriptional co-repressors that limit the response to TGFbeta signaling and play a role in regulating retinoic-acid-mediated gene expression. Mutations in human TGIF1 are associated with holoprosencephaly, but it is unclear whether this is a result of deregulation of TGFbeta/Nodal signaling, or of effects on other pathways. Surprisingly, mutation of Tgif1 in mice results in only relatively mild developmental phenotypes in most strain backgrounds.

Maternal Tgif is required for vascularization of the embryonic placenta.

The mammalian placenta is the site of exchange of nutrients and waste between mother and embryo. In humans, placental insufficiency can result in intrauterine growth retardation, perinatal death and spontaneous abortion. We show that in C57BL/6J mice a null mutation in the gene encoding the transcriptional corepressor, Tgif, causes placental defects.

The Tgif2 gene contains a retained intron within the coding sequence.

Background: TGIF and TGIF2 are homeodomain proteins, which act as TGFbeta specific Smad transcriptional corepressors. TGIF recruits general repressors including mSin3 and CtBP. The related TGIF2 protein functions in a similar manner, but does not bind CtBP.

TGIF inhibits retinoid signaling.

TGIF (TG-interacting factor) represses transforming growth factor beta (TGF-beta)-activated gene expression and can repress transcription via a specific retinoid response element. Mutations in human TGIF are associated with holoprosencephaly, a severe defect of craniofacial development with both genetic and environmental causes. Both TGF-beta and retinoic acid signaling are implicated in craniofacial development.

Multiple activities contribute to Pc2 E3 function.

Pc2 is a polycomb protein, which has SUMO E3 activity for the corepressors CtBP and CtBP2. Here we demonstrate that, in vivo, Pc2 adapter function contributes to enhancement of CtBP sumoylation. Mutation of the CtBP binding site on Pc2 abolishes E3 activity toward CtBP.

The polycomb protein Pc2 is a SUMO E3.

Polycomb group (PcG) proteins form large multimeric complexes (PcG bodies) which are involved in the stable repression of gene expression. The human PcG protein, Pc2, has been shown to recruit the transcriptional corepressor, CtBP, to PcG bodies. We show that CtBP is sumoylated at a single lysine.