Pbx1 Regulates Self-Renewal of Long-Term Hematopoietic Stem Cells by Maintaining Their Quiescence

Ficara, Francesca; Murphy, Mark; Lin, Min; Cleary, Michael L.

doi:10.1016/j.stem.2008.03.004

Cited by 212 publications

(238 citation statements)

References 42 publications

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“…Remarkably, analysis of Pbx1 −/− long-term hematopoietic stem cells showed that a significant fraction of Pbx1-regulated genes was associated with the TGF-β pathway (31).…”

Section: Discussionmentioning

confidence: 99%

Transcription factor PREP1 induces EMT and metastasis by controlling the TGF-β–SMAD3 pathway in non-small cell lung adenocarcinoma

Risolino

Mandia

Iavarone

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Pre-B-cell leukemia homeobox (Pbx)-regulating protein-1 (Prep1) is a ubiquitous homeoprotein involved in early development, genomic stability, insulin sensitivity, and hematopoiesis. Previously we have shown that Prep1 is a haploinsufficient tumor suppressor that inhibits neoplastic transformation by competing with myeloid ecotropic integration site 1 for binding to the common heterodimeric partner Pbx1. Epithelial-mesenchymal transition (EMT) is controlled by complex networks of proinvasive transcription factors responsive to paracrine factors such as TGF-β. Here we show that, in addition to inhibiting primary tumor growth, PREP1 is a novel EMT inducer and prometastatic transcription factor. In human non-small cell lung cancer (NSCLC) cells, PREP1 overexpression is sufficient to trigger EMT, whereas PREP1 down-regulation inhibits the induction of EMT in response to TGF-β. PREP1 modulates the cellular sensitivity to TGF-β by inducing the small mothers against decapentaplegic homolog 3 (SMAD3) nuclear translocation through mechanisms dependent, at least in part, on PREP1-mediated transactivation of a regulatory element in the SMAD3 first intron. Along with the stabilization and accumulation of PBX1, PREP1 induces the expression of multiple activator protein 1 components including the proinvasive Fos-related antigen 1 (FRA-1) oncoprotein. Both FRA-1 and PBX1 are required for the mesenchymal changes triggered by PREP1 in lung tumor cells. Finally, we show that the PREP1-induced mesenchymal transformation correlates with significantly increased lung colonization by cells overexpressing PREP1. Accordingly, we have detected PREP1 accumulation in a large number of human brain metastases of various solid tumors, including NSCLC. These findings point to a novel role of the PREP1 homeoprotein in the control of the TGF-β pathway, EMT, and metastasis in NSCLC.TALE proteins | PTGFβ P REP1 [pre-B-cell leukemia homeobox (Pbx)-regulating protein-1], also known as "PKNOX1" (PBX/knotted homeobox 1), belongs to the TALE (three-amino acid-loop-extension) family of homeodomain transcription factors, along with myeloid ecotropic integration site (MEIS) and PBX proteins. As indicated by its name, PREP1 retains PBX1 in the nucleus and induces its binding to DNA (1).PREP1 is essential in embryonic development. Although Prep1-null embryos die before gastrulation from apoptosis of the epiblast (2), hypomorphic Prep1-mutant mice (Prep i/i ), expressing severely decreased Prep1 levels (3-10% of wild-type) exhibit incompletely penetrant embryonic phenotypes, mainly characterized by alterations in hematopoiesis and angiogenesis (3).Prep1 deficiency affects cell proliferation and survival in various biological contexts. Decreased Prep1 expression results in increased apoptosis in Prep1 i/i embryos and mouse embryonic fibroblasts (MEFs) (4). In Prep1 −/− embryos, early preimplantation lethality is consequent to increased apoptosis in mouse pluripotent epiblast cells. Genetic analysis suggests that the lack of Prep1 confers increased sensitivity...

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“…Remarkably, analysis of Pbx1 −/− long-term hematopoietic stem cells showed that a significant fraction of Pbx1-regulated genes was associated with the TGF-β pathway (31).…”

Section: Discussionmentioning

confidence: 99%

Transcription factor PREP1 induces EMT and metastasis by controlling the TGF-β–SMAD3 pathway in non-small cell lung adenocarcinoma

Risolino

Mandia

Iavarone

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…We hypothesized that this was due to the short duration of treatment that resulted in up-regulation of genes below the significance threshold. To test this further, we examined the genes up-regulated by the combination treatment of forskolin and BMP4 and found a stronger activation of factors important for AGM HSC formation, such as Gata2 (Creyghton et al, 2010) and Gata3 (Fitch et al, 2012), as well as factors important for adult HSC maintenance such as Pbx1 (Ficara et al, 2008) compared with either treatment alone (Fig. 5 C).…”

Section: Global Transcriptome Shift Demonstrating Bmp Pathway Activationmentioning

confidence: 98%

Flow-induced protein kinase A–CREB pathway acts via BMP signaling to promote HSC emergence

Kim¹,

Nakano²,

Das³

et al. 2015

J Cell Biol

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Fluid shear stress promotes the emergence of hematopoietic stem cells (HSCs) in the aortagonad-mesonephros (AGM) of the developing mouse embryo. We determined that the AGM is enriched for expression of targets of protein kinase A (PKA)-cAMP response elementbinding protein (CREB), a pathway activated by fluid shear stress. By analyzing CREB genomic occupancy from chromatin-immunoprecipitation sequencing (ChIP-seq) data, we identified the bone morphogenetic protein (BMP) pathway as a potential regulator of CREB. By chemical modulation of the PKA-CREB and BMP pathways in isolated AGM VEcadherin + cells from mid-gestation embryos, we demonstrate that PKA-CREB regulates hematopoietic engraftment and clonogenicity of hematopoietic progenitors, and is dependent on secreted BMP ligands through the type I BMP receptor. Finally, we observed blunting of this signaling axis using Ncx1-null embryos, which lack a heartbeat and intravascular flow. Collectively, we have identified a novel PKA-CREB-BMP signaling pathway downstream of shear stress that regulates HSC emergence in the AGM via the endothelial-tohematopoietic transition.

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“…Scl-deficient HSCs exhibited impaired long-term activity with increased cycling HSCs [89]. Conditional pre-B cell leukemia transcription factor 1 (PBX1) deletion in HSCs impaired the self-renewal capacity in HSCs, as shown by secondary transplantation [90]. The overexpression of early growth response 1 (Egr1) in HSCs suppressed the differentiation into the granulocyte and erythroid lineages [91].…”

Section: Transcription Factors Regulating Hscsmentioning

confidence: 99%

Mechanisms of self-renewal in hematopoietic stem cells

Wang

Ema

2015

Int J Hematol

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Pbx1 Regulates Self-Renewal of Long-Term Hematopoietic Stem Cells by Maintaining Their Quiescence

Cited by 212 publications

References 42 publications

Transcription factor PREP1 induces EMT and metastasis by controlling the TGF-β–SMAD3 pathway in non-small cell lung adenocarcinoma

Transcription factor PREP1 induces EMT and metastasis by controlling the TGF-β–SMAD3 pathway in non-small cell lung adenocarcinoma

Flow-induced protein kinase A–CREB pathway acts via BMP signaling to promote HSC emergence

Mechanisms of self-renewal in hematopoietic stem cells

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