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Prep1 and Meis1 competition for Pbx1 binding regulates protein stability and tumorigenesis

ABSTRACT: This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

ORGANISM(S): Mus musculus

SUBMITTER: Leila Dardaei

PROVIDER: E-GEOD-82135 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Prep1 and Meis1 competition for Pbx1 binding regulates protein stability and tumorigenesis.

Project description:Prep1 is a tumor-suppressor, whereas Meis1 is an oncogene. We show that to perform these activities in MEFs both proteins competitively hetero-dimerize with Pbx1. Meis1 alone transforms Prep1-deficient fibroblasts while Prep1 overexpression inhibits Meis1 tumorigenicity. Pbx1 can therefore alternatively act as oncogene or tumor-suppressor. Prep1 post-translationally controls the level of Meis1 decreasing its stability by sequestering Pbx1. The different levels of Meis1 and the presence of Prep1 are followed at the transcriptional level by the induction of specific transcriptional signatures. The decrease of Meis1 prevents Meis1 interaction with Ddx3x and Ddx5, which are essential for Meis1 tumorigenesis, and modifies the growth promoting DNA binding landscape of Meis1 to the growth controlling landscape of Prep1. Hence the key feature of Prep1 tumor inhibiting activity is the control of Meis1 stability. Examination of Prep1 and Meis1 in three cell type

2014-03-05 | E-GEOD-54221 | biostudies-arrayexpress

Prep1 and Meis1 competition for Pbx1 binding regulates protein stability and tumorigenesis [hP]

2016-06-01 | E-GEOD-58802 | biostudies-arrayexpress

Meis1 induces and Prep1 suppresses tumors by exploiting low affinity AP1 binding sites.

Project description:We have defined the tumor and tumor suppressor signature for Meis1 and Prep1 (pKnox1), respectively, using ChIP-seq and RNA-seq in a cell system in which tumor suppressor Prep1 and oncogene Meis1 compete for tumorigenesis [GSE54221; GSE58802]. In this paper we report that the number of Meis1 or Prep1 DNA binding sites increases linearly with the level of expression of the two transcription factors. Overexpression of Meis1 induces tumors. At the molecular level it modifies the DNA target specificity by increasing the number of low-affinity binding sites, which results in a different choice of consensus sequences with predominance of sites normally bound by the AP1 transcription factor family. Upon concomitant overexpression of Prep1 and Meis1 tumorigenesis is inhibited. Prep1 dominates over Meis1 not only because it partially decreases Meis1 protein level but also because it prevents the binding to a substantial fraction of the low affinity binding sites. Overall, overexpression of Prep1 reverses the nature of the bound and regulated genes from stimulatory to inhibitory of signal transduction and transcription, which suppresses tumorigenesis. By identifying the Meis1 tumor signature, specific relevant signaling pathways are identified. In line with these results, tumorigenic Meis1-overexpressing cells are uniquely hypersensitive to inhibitors of the MAPK/Akt pathways. Examination of Prep1 and Meis1 in five cell type

2016-06-25 | E-GEOD-58818 | biostudies-arrayexpress

ChIP-seq of Pbx1, Prep1 and Sp2 in WT MEFs, Sp2ko MEFs and in Sp2ko MEFs ectopically expressing Flag-tagged full length Sp2; and ChIPexo of Sp2 in WT and Sp2ko MEFs

Project description:We investigated the genomic binding profiles of the transcription factors Pbx1, Prep1, and Sp2 in mouse embryonic fibroblasts using ChIPseq and ChIPexo. Refer to E-MTAB-2970 and E-MTAB-994 for KO and IgG Controls.

2018-10-17 | E-MTAB-7125 | biostudies-arrayexpress

TALE transcription factors binding and transcriptional effect [RNA-Seq]

Project description:Meis, Prep and Pbx1 TALE homeoproteins interactions with Hox proteins are essential for development and disease. Although Meis and Prep behave similarly in vitro, their in vivo activities remain largely unexplored. We show that Prep and Meis interact with largely independent sets of genomic sites and select different DNA binding sequences, with Prep associating mostly with promoters and house-keeping genes and Meis with promoter-remote regions and developmental genes. Hox target sequences associate strongly with Meis but not with Prep binding sites, while Pbx1 cooperates with both Prep and Meis. Accordingly, Meis1 shows strong genetic interaction with Pbx1 but not with Prep1. Meis1 and Prep1 nonetheless co-regulate a subset of genes, predominantly through opposing effects. Notably, the TALE homeoprotein binding profile subdivides Hox clusters into two domains differentially regulated by Meis1 and Prep1. After duplication of the ancestral gene, Meis and Prep thus specialized their interactions but maintained significant regulatory coordination. RNA-seq of 2 Meis1 and Prep1 loss of function mutants in E11.5 C57BL/6 embryonic mice

2013-03-31 | E-GEOD-39605 | biostudies-arrayexpress

TALE transcription factors binding and transcriptional effect

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2013-03-31 | E-GEOD-39609 | biostudies-arrayexpress

Prep1 and Meis1 competition for Pbx1 binding regulates protein stability and tumorigenesis.

Project description:Pbx-regulating protein-1 (Prep1) is a tumor suppressor, whereas myeloid ecotropic viral integration site-1 (Meis1) is an oncogene. We show that, to perform these activities in mouse embryonic fibroblasts, both proteins competitively heterodimerize with pre-B-cell leukemia homeobox-1 (Pbx1). Meis1 alone transforms Prep1-deficient fibroblasts, whereas Prep1 overexpression inhibits Meis1 tumorigenicity. Pbx1 can, therefore, alternatively act as an oncogene or tumor suppressor. Prep1 posttranslationally controls the level of Meis1, decreasing its stability by sequestering Pbx1. The different levels of Meis1 and the presence of Prep1 are followed at the transcriptional level by the induction of specific transcriptional signatures. The decrease of Meis1 prevents Meis1 interaction with Ddx3x and Ddx5, which are essential for Meis1 tumorigenesis, and modifies the growth-promoting DNA binding landscape of Meis1 to the growth-controlling landscape of Prep1. Hence, the key feature of Prep1 tumor-inhibiting activity is the control of Meis1 stability.

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MEIS1, PREP1, and PBX4 are differentially expressed in acute lymphoblastic leukemia: association of MEIS1 expression with higher proliferation and chemotherapy resistance.

Project description:BackgroundThe Three-amino acid-loop-extension (TALE) superfamily of homeodomain-containing transcription factors have been implicated in normal hematopoiesis and in leukemogenesis and are important survival, differentiation, and apoptosis pathway modulators. In this work, we determined the expression levels of TALE genes in leukemic-derived cell lines, in blood samples of patients with Acute lymphoblastic leukemia (ALL), and in the blood samples of healthy donors.ResultsHere we show increased expression of MEIS1, MEIS2, and PREP1 genes in leukemia-derived cell lines compared with blood normal cells. High levels of MEIS1 and PREP1, and low levels of PBX4 expression were also founded in samples of patients with ALL. Importantly, silencing of MEIS1 decreases the proliferation of leukemia-derived cells but increases their survival after etoposide treatment. Etoposide-induced apoptosis induces down-regulation of MEIS1 expression or PREP1 up-regulation in chemotherapy-resistant cells.ConclusionsOur results indicate that up-regulation of MEIS1 is important for sustaining proliferation of leukemic cells and that down-regulation of MEIS1 or up-regulation of PREP1 and PBX genes could be implicated in the modulation of the cellular response to chemotherapeutic-induced apoptosis.

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Identification of NKX2-5 transcriptional targets in the mouse embryonic heart

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2015-09-02 | E-GEOD-44576 | biostudies-arrayexpress

Prep1 and Meis1 competition for Pbx1 binding regulates protein stability and tumorigenesis

Project description:This SuperSeries is composed of the SubSeries listed below.

2016-06-01 | GSE82135 | GEO