Cooperative Transcriptional Activation by Klf4, Meis2, and Pbx1

Department of Biochemistry and Molecular Genetics and Center for Cell Signaling, University of Virginia, Charlottesville, Virginia 22908, USA.
Molecular and Cellular Biology (Impact Factor: 4.78). 07/2011; 31(18):3723-33. DOI: 10.1128/MCB.01456-10
Source: PubMed


The Kruppel-like factor Klf4 is implicated in tumorigenesis and maintaining stem cell pluripotency, and Klf4 can both activate
and repress gene expression. We show that the Pbx1 and Meis2 homeodomain proteins interact with Klf4 and can be recruited
to DNA elements comprising a Klf4 site or GC box, with adjacent Meis and Pbx sites. Meis2d and Pbx1a activate expression of
p15Ink4a and E-cadherin, dependent on the Meis2d transcriptional activation domain. In HepG2 cells, reducing expression of endogenous
Meis2 or Pbx1 decreases p15 gene expression and increases the number of cells entering S phase. Although DNA binding by all
three proteins contributes to full cooperative activation, the sequence requirements for binding by Meis2 and Pbx1 are variable.
In the E-cadherin promoter, a Pbx-like site is required for full activation, whereas in the p15 promoter, the Klf4 site appears
to play the major role. Through a bioinformatics search we identified additional genes with conserved binding sites for Klf4,
Meis2, and Pbx1 and show that at least some of these genes can be activated cooperatively by Klf4 and Meis2/Pbx1. We suggest
a model in which genes with Klf4 sites can be cooperatively activated by Meis2/Pbx1 and Klf4, dependent primarily on recruitment
by Klf4. This provides a mechanism to modulate transcriptional regulation by the multifunctional Klf4 transcription factor.

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    • "Meis2b isoform " 3 " is required for the activity of a PDX1:PBX1b:MEIS2b complex in pancreatic acinar cells involved in the transcriptional activation of the ELA1 enhancer; the complex binds to the enhancer B element and cooperates with the transcription factor 1 complex (PTF1) bound to the enhancer A element (Liu et al., 2001). Probably in complex with PBX1, MEIS2 isoform d is involved in transcriptional activity of KLF4 (Bjerke et al., 2011). In cooperation with a PBX protein (such as PBX2), MEIS isoform " 2b " has been proposed to act in the transcriptional activation of EPHA8 in the developing midbrain (Shim et al., 2007). "
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    ABSTRACT: TALE (three amino acids loop extension) homeodomain transcription factors are required in various steps of embryo development, in many adult physiological functions and are involved in important pathologies. This review focuses on the PREP, MEIS and PBX sub-families of TALE factors and aims at giving information on their biochemical properties, i.e. structure, interactors and interaction surfaces. Members of the three sets of protein form dimers in which the common partner is PBX but they can also directly interact with other proteins forming higher-order complexes, in particular HOX. Finally, recent advances in determining the genome-wide DNA-binding sites of PREP1, MEIS1 and PBX1, and their partial correspondence with the binding sites of some HOX proteins, are reviewed. These studies have generated a few general rules that can be applied to all members of the three gene families. PREP and MEIS recognize slightly different consensus sequences: PREP prefers to bind to promoters and to have PBX as a DNA-binding partner; MEIS prefers HOX as partner, and both PREP and MEIS drive PBX to their own binding sites. This outlines the clear individuality of the PREP and MEISs proteins, the former mostly devoted to basic cellular functions, the latter more to developmental functions. Developmental Dynamics, 2013. © 2013 Wiley Periodicals, Inc.
    Developmental Dynamics 01/2014; 243(1). DOI:10.1002/dvdy.24016 · 2.38 Impact Factor
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    • "PBX1 gene is a bad prognostic factor in MM. PBX1 interacts with MEIS to bind to DNA element [31]. PBX1 gene is fused to the transcription factor E2A as a result of the t(1;19) translocation in pre-B cell leukemia [32]. "
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    ABSTRACT: Gene expression-based scores used to predict risk in cancer frequently include genes coding for DNA replication, repair or recombination. Using two independent cohorts of 206 and 345 previously-untreated patients with Multiple Myeloma (MM), we identified 50 cell cycle-unrelated genes overexpressed in multiple myeloma cells (MMCs) compared to normal human proliferating plasmablasts and non-proliferating bone marrow plasma cells and which have prognostic value for overall survival. Thirty-seven of these 50 myeloma genes (74%) were enriched in genes overexpressed in one of 3 normal human stem cell populations--pluripotent (18), hematopoietic (10) or mesenchymal stem cells (9)--and only three genes were enriched in one of 5 populations of differentiated cells (memory B lymphocytes, T lymphocytes, polymorphonuclear cells, monocytes, osteoclasts). These 37 genes shared by MMCs and adult or pluripotent stem cells were used to build a stem cell score ((SC)score), which proved to be strongly prognostic in the 2 independent cohorts of patients compared to other gene expression-based risk scores or usual clinical scores using multivariate Cox analysis. This finding highlights cell cycle-unrelated prognostic genes shared by myeloma cells and normal stem cells, whose products might be important for normal and malignant stem cell biology.
    PLoS ONE 07/2012; 7(7):e42161. DOI:10.1371/journal.pone.0042161 · 3.23 Impact Factor
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    ABSTRACT: The molecular determinants of spleen organogenesis and the etiology of isolated congenital asplenia (ICA), a life-threatening human condition, are unknown. We previously reported that Pbx1 deficiency causes organ growth defects including asplenia. Here, we show that mice with splenic mesenchyme-specific Pbx1 inactivation exhibit hyposplenia. Moreover, the loss of Pbx causes downregulation of Nkx2-5 and derepression of p15Ink4b in spleen mesenchymal progenitors, perturbing the cell cycle. Removal of p15Ink4b in Pbx1 spleen-specific mutants partially rescues spleen growth. By whole-exome sequencing of a multiplex kindred with ICA, we identify a heterozygous missense mutation (P236H) in NKX2-5 showing reduced transactivation in vitro. This study establishes that a Pbx/Nkx2-5/p15 regulatory module is essential for spleen development.
    Developmental Cell 05/2012; 22(5):913-26. DOI:10.1016/j.devcel.2012.02.009 · 9.71 Impact Factor
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