Browse
Submit Data
Databases
API
Help

Dataset Information

28 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Homeodomain transcription factor and tumor suppressor Prep1 is required to maintain genomic stability.

ABSTRACT: Prep1 is a homeodomain transcription factor that is essential in embryonic development and functions in the adult as a tumor suppressor. We show here that Prep1 is involved in maintaining genomic stability and preventing neoplastic transformation. Hypomorphic homozygous Prep1(i/i) fetal liver cells and mouse embryonic fibroblasts (MEFs) exhibit increased basal DNA damage and normal DNA damage response after γ-irradiation compared with WT. Cytogenetic analysis shows the presence of numerous chromosomal aberrations and aneuploidy in very early-passage Prep1(i/i) MEFs. In human fibroblasts, acute Prep1 down-regulation by siRNA induces DNA damage response, like in Prep1(i/i) MEFs, together with an increase in heterochromatin-associated modifications: rapid increase of histone methylation and decreased transcription of satellite DNA. Ectopic expression of Prep1 rescues DNA damage and heterochromatin methylation. Inhibition of Suv39 activity blocks the chromatin but not the DNA damage phenotype. Finally, Prep1 deficiency facilitates cell immortalization, escape from oncogene-induced senescence, and H-Ras(V12)-dependent transformation. Importantly, the latter can be partially rescued by restoration of Prep1 level. The results show that the tumor suppressor role of Prep1 is associated with the maintenance of genomic stability.

SUBMITTER: Iotti G

PROVIDER: S-EPMC3141938 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Loss of the Homeodomain Transcription Factor Prep1 Perturbs Adult Hematopoiesis in the Bone Marrow.

Project description:Prep1, a TALE-family homeodomain transcription factor, has been demonstrated to play a critical role in embryonic hematopoiesis, as its insufficiency caused late embryonic lethality associated with defective hematopoiesis and angiogenesis. In the present study, we generated hematopoietic- and endothelial cell-specific Prep1-deficient mice and demonstrated that expression of Prep1 in the hematopoietic cell compartment is not essential for either embryonic or adult hematopoiesis, although its absence causes significant hematopoietic abnormalities in the adult bone marrow. Loss of Prep1 promotes cell cycling of hematopoietic stem/progenitor cells (HSPC), leading to the expansion of the HSPC pool. Prep1 deficiency also results in the accumulation of lineage-committed progenitors, increased monocyte/macrophage differentiation and arrested erythroid maturation. Maturation of T cells and B cells is also perturbed in Prep-deficient mice. These findings provide novel insight into the pleiotropic roles of Prep1 in adult hematopoiesis that were unrecognized in previous studies using germline Prep1 hypomorphic mice.

| S-EPMC4540428 | biostudies-literature

Germ cell-intrinsic requirement for the homeodomain transcription factor PKnox1/Prep1 in adult spermatogenesis.

Project description:PKnox1 (also known as Prep1) belongs to the TALE family of homeodomain transcription factors that are critical for regulating growth and differentiation during embryonic and postnatal development in vertebrates. We demonstrate here that PKnox1 is required for adult spermatogenesis in a germ cell-intrinsic manner. Tamoxifen-mediated PKnox1 loss in the adult testes, as well as its germ cell-specific ablation, causes testis hypotrophy with germ cell apoptosis and, as a consequence, compromised spermatogenesis. In PKnox1-deficient testes, spermatogenesis was arrested at the c-Kit+ spermatogonia stage, with a complete loss of the meiotic spermatocytes, and was accompanied by compromised differentiation of the c-Kit+ spermatogonia. Taken together, these results indicate that PKnox1 is a critical regulator of maintenance and subsequent differentiation of the c-Kit+ stage of spermatogonia in the adult testes.

| S-EPMC5749842 | biostudies-literature

New Insights into Cooperative Binding of Homeodomain Transcription Factors PREP1 and PBX1 to DNA.

Project description:PREP1 and PBX1 are homeodomain (HD) transcription factors that play crucial roles in embryonic development. Here, we present the first biophysical characterization of a PREP1 HD, and the NMR spectroscopic study of its DNA binding pocket. The data show that residues flanking the HD participate in DNA binding. The kinetic parameters for DNA binding of individual PREP1 and PBX1 HDs, and of their combination, show that isolated PREP1 and PBX1 HDs bind to DNA in a cooperative manner. A novel PREP1 motif, flanking the HD at the C-terminus, is required for cooperativity.

| S-EPMC5240567 | biostudies-literature

Prep1 (pKnox1)-deficiency leads to spontaneous tumor development in mice and accelerates EmuMyc lymphomagenesis: a tumor suppressor role for Prep1.

Project description:The Prep1 homeodomain transcription factor is essential for embryonic development. 25% of hypomorphic Prep1(i/i) embryos, expressing the gene at 2% of the normal levels, survive pregnancy and live a normal-length life. Later in life, however, these mice develop spontaneous pre-tumoral lesions or solid tumors (lymphomas and carcinomas). In addition, transplantation of E14.5 fetal liver (FL) Prep1(i/i) cells into lethally irradiated mice induces lymphomas. In agreement with the above data, haploinsufficiency of a different Prep1-deficient (null) allele accelerates EmuMyc lymphoma growth. Therefore Prep1 has a tumor suppressor function in mice. Immunohistochemistry on tissue micrroarrays (TMA) generated from three distinct human cohorts comprising a total of some 1000 human tumors revealed that 70% of the tumors express no or extremely low levels of Prep1, unlike normal tissues. Our data in mice are thus potentially relevant to human cancer.

| S-EPMC5527898 | biostudies-literature

Identification of homeodomain proteins, PBX1 and PREP1, involved in the transcription of murine leukemia virus.

Project description:Cyclin-dependent kinase inhibitors (CDKIs) have been shown to block human immunodeficiency virus and herpes simplex virus. It is hypothesized that CDKIs block viral replication by inhibiting transcription of specific cellular genes. Here we find that three CDKIs, flavopiridol, purvalanol A, and methoxy-roscovitine, block Moloney murine leukemia virus (MLV) transcription events. Using gene expression microarray technology to examine the inhibitory effects of CDKIs, we observed a cellular gene, the pre-B-cell leukemia transcription factor 1 (Pbx1) gene, down-regulated by CDKI treatment. The PBX consensus element (PCE), TGATTGAC, is conserved in the long terminal repeats of several murine retroviruses, including Moloney MLV. Mutations in the PCE completely inhibited viral transcription whereas overexpression of PBX1 and a PBX1-associated protein, PREP1, enhanced viral transcription. The interaction between the PCE and PBX1-PREP1 proteins was confirmed by gel shift experiments. Blocking PBX1 protein synthesis resulted in a significant decrease in viral transcription. Collectively, our results represent the first work demonstrating that the homeodomain proteins PBX1 and PREP1 are cellular factors involved in Moloney MLV transcription regulation.

| S-EPMC140703 | biostudies-literature

Tumor suppressor TAp73 is required to maintain pluripotency of cancer stem cells

Project description:Cancer stem cells (CSCs) are resistant to conventional chemotherapy and are hence responsible for cancer relapse. Pluripotency is a characteristic of CSCs which allows them to rapidly proliferate while maintaining the ability to differentiate into various lineages. We found that TAp73, but not its homologue p53, is required for the pluripotency of CSCs. TAp73 knockdown (KD) decreased SOD1 levels, increased ROS production and disturbed metabolism which induced differentiation and abrogated pluripotency in CSCs. TAp73 related decrease in pluripotency is linked to increased autophagy and senescence in CSCs. Furthermore, TAp73 KD also decreased the levels of pluripotency factor Sox-2 within heterogeneous cancer cell lines. Interestingly, TAp73-deficient CSCs strongly lose tumorigenic potential in mice and tumors that did form had significantly lower levels of SOD1 and pluripotency marker Oct4. Our findings reveal a unique role of TAp73 in CSCs development that is important to consider while devising future therapeutic strategies against cancer.

2019-03-05 | PXD005407 | Pride

MLL4 Is Required to Maintain Broad H3K4me3 Peaks and Super-Enhancers at Tumor Suppressor Genes.

Project description:Super-enhancers are large clusters of enhancers that activate gene expression. Broad trimethyl histone H3 lysine 4 (H3K4me3) often defines active tumor suppressor genes. However, how these epigenomic signatures are regulated for tumor suppression is little understood. Here we show that brain-specific knockout of the H3K4 methyltransferase MLL4 (a COMPASS-like enzyme, also known as KMT2D) in mice spontaneously induces medulloblastoma. Mll4 loss upregulates oncogenic Ras and Notch pathways while downregulating neuronal gene expression programs. MLL4 enhances DNMT3A-catalyzed DNA methylation and SIRT1/BCL6-mediated H4K16 deacetylation, which antagonize expression of Ras activators and Notch pathway components, respectively. Notably, Mll4 loss downregulates tumor suppressor genes (e.g., Dnmt3a and Bcl6) by diminishing broad H3K4me3 and super-enhancers and also causes widespread impairment of these epigenomic signatures during medulloblastoma genesis. These findings suggest an anti-tumor role for super-enhancers and provide a unique tumor-suppressive mechanism in which MLL4 is necessary to maintain broad H3K4me3 and super-enhancers at tumor suppressor genes.

| S-EPMC6528658 | biostudies-literature

Physiological levels of reactive oxygen species are required to maintain genomic stability in stem cells.

Project description:Stem cell cytogenetic abnormalities constitute a roadblock to regenerative therapies. We investigated the possibility that reactive oxygen species (ROSs) influence genomic stability in cardiac and embryonic stem cells. Karyotypic abnormalities in primary human cardiac stem cells were suppressed by culture in physiological (5%) oxygen, but addition of antioxidants to the medium unexpectedly increased aneuploidy. Intracellular ROS levels were moderately decreased in physiological oxygen, but dramatically decreased by the addition of high-dose antioxidants. Quantification of DNA damage in cardiac stem cells and in human embryonic stem cells revealed a biphasic dose-dependence: antioxidants suppressed DNA damage at low concentrations, but potentiated such damage at higher concentrations. High-dose antioxidants decreased cellular levels of ATM (ataxia-telangiectasia mutated) and other DNA repair enzymes, providing a potential mechanistic basis for the observed effects. These results indicate that physiological levels of intracellular ROS are required to activate the DNA repair pathway for maintaining genomic stability in stem cells. The concept of an "oxidative optimum" for genomic stability has broad implications for stem cell biology and carcinogenesis.

| S-EPMC3408073 | biostudies-literature

Piecing Together How Peroxiredoxins Maintain Genomic Stability.

Project description:Peroxiredoxins, a highly conserved family of thiol oxidoreductases, play a key role in oxidant detoxification by partnering with the thioredoxin system to protect against oxidative stress. In addition to their peroxidase activity, certain types of peroxiredoxins possess other biochemical activities, including assistance in preventing protein aggregation upon exposure to high levels of oxidants (molecular chaperone activity), and the transduction of redox signals to downstream proteins (redox switch activity). Mice lacking the peroxiredoxin Prdx1 exhibit an increased incidence of tumor formation, whereas baker's yeast (Saccharomyces cerevisiae) lacking the orthologous peroxiredoxin Tsa1 exhibit a mutator phenotype. Collectively, these findings suggest a potential link between peroxiredoxins, control of genomic stability, and cancer etiology. Here, we examine the potential mechanisms through which Tsa1 lowers mutation rates, taking into account its diverse biochemical roles in oxidant defense, protein homeostasis, and redox signaling as well as its interplay with thioredoxin and thioredoxin substrates, including ribonucleotide reductase. More work is needed to clarify the nuanced mechanism(s) through which this highly conserved peroxidase influences genome stability, and to determine if this mechanism is similar across a range of species.

| S-EPMC6316004 | biostudies-literature

Elongation Factor TFIIS Prevents Transcription Stress and R-Loop Accumulation to Maintain Genome Stability.

Project description:Although correlations between RNA polymerase II (RNAPII) transcription stress, R-loops, and genome instability have been established, the mechanisms underlying these connections remain poorly understood. Here, we used a mutant version of the transcription elongation factor TFIIS (TFIISmut), aiming to specifically induce increased levels of RNAPII pausing, arrest, and/or backtracking in human cells. Indeed, TFIISmut expression results in slower elongation rates, relative depletion of polymerases from the end of genes, and increased levels of stopped RNAPII; it affects mRNA splicing and termination as well. Remarkably, TFIISmut expression also dramatically increases R-loops, which may form at the anterior end of backtracked RNAPII and trigger genome instability, including DNA strand breaks. These results shed light on the relationship between transcription stress and R-loops and suggest that different classes of R-loops may exist, potentially with distinct consequences for genome stability.

| S-EPMC6863433 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data