Hypomorphic Mutation of the TALE Gene <i>Prep1</i> (<i>pKnox1</i>) Causes a Major Reduction of Pbx and Meis Proteins and a Pleiotropic Embryonic Phenotype

Ferretti, Elisabetta; Villaescusa, J. Carlos; Rosa, Patrizia; Fernandez-Díaz, Luis C.; Longobardi, Elena; Mazzieri, Roberta; Miccio, Annarita; Micali, Nicola; Selleri, Licia; Ferrari, G.; Blasi, Francesco

doi:10.1128/mcb.00313-06

Cited by 102 publications

(166 citation statements)

References 57 publications

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“…Prep1 i/i mice and embryos have been described (2). E14.5 WT and Prep1 i/i MEFs were cultured under low oxygen tension.…”

Section: Methodsmentioning

confidence: 99%

“…T ranscription factor Prep1 belongs to the 3aa-loop extension class of homeodomain proteins and is essential at multiple stages of embryonic development (1)(2)(3)(4). Prep1 is ubiquitously expressed both in developing and adult mice and can form tripartite DNA-binding complexes with members of the Hox and Pbx protein families (5)(6)(7).…”

mentioning

confidence: 99%

“…Mouse embryos carrying a hypomorphic Prep1 i/i mutation (expressing 2% mRNA and 3-7% protein compared with WT) show general organ hypoplasia and in 75% of cases, die at about embryonic day E17.5 with major alterations in hematopoiesis, angiogenesis, and eye development (2,10). Furthermore, Prep1 i/i mouse embryonic fibroblasts (MEFs) show increased basal and genotoxic stress-induced apoptosis (11).…”

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confidence: 99%

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

Iotti

Longobardi

Masella

et al. 2011

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

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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 oncogeneinduced 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.

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“…Prep1 i/i mice and embryos have been described (2). E14.5 WT and Prep1 i/i MEFs were cultured under low oxygen tension.…”

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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

Iotti

Longobardi

Masella

et al. 2011

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

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“…However, expression of anterior HoxB genes also depends on an auto-regulatory circuit involving the HoxB1 protein and the Prep1-Pbx1 complex (Marshall et al, 1996;Maconochie et al, 1997;Dupe et al, 1999;Jacobs et al, 1999;Ryoo et al, 1999;Ferretti et al, 2000Ferretti et al, , 2005Huang et al, 2002). Prep1 and Pbx1 are essential genes in embryonic development (Selleri et al, 2001;Waskiewicz et al, 2002;Deflorian et al, 2004;Penkov et al, 2005;Ferretti et al, 2006;Di Rosa et al, 2007). Unlike monomeric Prep1 and Pbx1, dimeric Prep1-Pbx1 complexes bind DNA and interact with HoxB1 to activate HoxB1 and HoxB2 transcription This article was published online ahead of print in MBC in Press (http://www.molbiolcell.org/cgi/doi/10.1091/mbc.E09 -02-0114) on May 28, 2009.…”

Section: Introductionmentioning

confidence: 99%

Induction of HoxB Transcription by Retinoic Acid Requires Actin Polymerization

Ferrai

Naum-Onganía

Longobardi

et al. 2009

MBoC

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We have analyzed the role of actin polymerization in retinoic acid (RA)-induced HoxB transcription, which is mediated by the HoxB regulator Prep1. RA induction of the HoxB genes can be prevented by the inhibition of actin polymerization. Importantly, inhibition of actin polymerization specifically affects the transcription of inducible Hox genes, but not that of their transcriptional regulators, the RARs, nor of constitutively expressed, nor of actively transcribed Hox genes. RA treatment induces the recruitment to the HoxB2 gene enhancer of a complex composed of "elongating" RNAPII, Prep1, ␤-actin, and N-WASP as well as the accessory splicing components p54Nrb and PSF. We show that inhibition of actin polymerization prevents such recruitment. We conclude that inducible Hox genes are selectively sensitive to the inhibition of actin polymerization and that actin polymerization is required for the assembly of a transcription complex on the regulatory region of the Hox genes.

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“…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).…”

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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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Hypomorphic Mutation of the TALE Gene Prep1 (pKnox1) Causes a Major Reduction of Pbx and Meis Proteins and a Pleiotropic Embryonic Phenotype

Cited by 102 publications

References 57 publications

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

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

Induction of HoxB Transcription by Retinoic Acid Requires Actin Polymerization

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

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