Prep1 (pKnox1)‐deficiency leads to spontaneous tumor development in mice and accelerates EμMyc lymphomagenesis: A tumor suppressor role for Prep1

Longobardi, Elena; Iotti, Giorgio; Rosa, Patrizia; Mejetta, Stefania; Bianchi, Fabrizio; Fernandez-Díaz, Luis C.; Micali, Nicola; Nuciforo, Paolo; Lenti, Elisa; Ponzoni, Maurilio; Doglioni, Claudio; Caniatti, M.; Fiore, Pier Paolo Di; Blasi, Francesco

doi:10.1016/j.molonc.2010.01.001

Cited by 42 publications

(62 citation statements)

References 30 publications

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“…Because genomic instability highly increases the chance of accumulating genetic mutations, leading to cancer development (50), the present work provides a cellular basis for the identified tumor-suppressor activity of Prep1 (12). Indeed, we present evidence that the reduction of Prep1 compromises checkpoint mechanisms involved in limiting oncogene-induced transformation (Fig.…”

Section: Discussionmentioning

confidence: 62%

“…S5B). It is interesting to notice that, in mammals, although Prep1 is a tumor suppressor (12), the other Hth ortholog Meis1 is, in fact, an oncogene, at least in hematopoietic malignancies (46,47).…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, Prep1 i/i mouse embryonic fibroblasts (MEFs) show increased basal and genotoxic stress-induced apoptosis (11). Remarkably, the homozygous Prep1 i/i hypomorphic mice that survive embryonic lethality are prone to develop tumors late in life, suggesting that Prep1 may be a tumor suppressor in mice (12). Indeed, Prep1 haploinsufficiency accelerates the development of the EμMyc lymphomas, and a survey of human cancers shows a dramatic reduction of Prep1 expression in a large proportion (70%) of the patients (12).…”

mentioning

confidence: 99%

“…The late development of tumors in the Prep1 i/i hypomorphic mice surviving embryonic lethality (12), the p53-dependent apoptosis of the Prep1-null epiblast (4), and the apoptosis in the Prep1 i/i MEFs (11) suggest that genetic instability might be a basic cellular phenotype associated with Prep1 down-regulation/absence.…”

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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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Section: Discussionmentioning

confidence: 62%

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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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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“…In addition, surviving Prep i/i mice develop spontaneous pretumoral lesions and eventually lymphomas and carcinomas. Accordingly, we have detected very low PREP1 expression in a majority of specimens representing a wide range of human tumors (8).…”

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confidence: 82%

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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A tale of TALE, PREP1, PBX1, and MEIS1: Interconnections and competition in cancer

et al. 2017

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We report the latest structural information on PREP1 tumor suppressor, the specific ''oncogene'' and ''tumor suppressive'' signatures of MEIS1 and PREP1, the molecular rules regulating PREP1 and MEIS1 binding to DNA, and how these can change depending on the interaction with PBX1, cell-type, neoplastic transformation, and intracellular concentration. As both PREP1 and MEIS1 interact with PBX1 they functionally compete with each other. PREP1, PBX1, and MEIS1 TALE-class homeodomain transcription factors act in an interdependent and integrated way in experimental tumorigenesis. We also pool together the plethora of data available in human cancer databanks and connect them with the available molecular information. The emerging picture suggests that a similarly basic approach might be used to better dissect and define other oncogenes and suppressors and better understand human cancer.

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Prep1 (pKnox1)‐deficiency leads to spontaneous tumor development in mice and accelerates EμMyc lymphomagenesis: A tumor suppressor role for Prep1

Cited by 42 publications

References 30 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

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

A tale of TALE, PREP1, PBX1, and MEIS1: Interconnections and competition in cancer

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