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

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 Prep1i/i fetal liver cells an... Full description

Journal Title: Proceedings of the National Academy of Sciences of the United States of America July 19, 2011, Vol.108(29), pp.E314-E322
Main Author: Iotti, Giorgio
Other Authors: Longobardi, Elena , Masella, Silvia , Dardaei, Leila , De Santis, Francesca , Micali, Nicola , Blasi, Francesco
Format: Electronic Article Electronic Article
Language: English
Subjects:
ID: E-ISSN: 1091-6490 ; DOI: 10.1073/pnas.1105216108
Link: http://search.proquest.com/docview/878597360/?pq-origsite=primo
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title: Homeodomain transcription factor and tumor suppressor Prep1 is required to maintain genomic stability.
format: Article
creator:
  • Iotti, Giorgio
  • Longobardi, Elena
  • Masella, Silvia
  • Dardaei, Leila
  • De Santis, Francesca
  • Micali, Nicola
  • Blasi, Francesco
subjects:
  • Animals–Metabolism
  • Cell Transformation, Neoplastic–Genetics
  • Chromatin Immunoprecipitation–Cytology
  • Comet Assay–Metabolism
  • Cytogenetic Analysis–Genetics
  • DNA Damage–Physiology
  • Embryo, Mammalian–Physiology
  • Fibroblasts–Genetics
  • Gamma Rays–Radiation Effects
  • Gene Expression Regulation–Metabolism
  • Genomic Instability–Physiology
  • Heterochromatin–Genetics
  • Homeodomain Proteins–Metabolism
  • Humans–Physiology
  • Mice–Physiology
  • Oligonucleotides–Physiology
  • Transcription Factors–Physiology
  • Heterochromatin
  • Homeodomain Proteins
  • Oligonucleotides
  • Pknox1 Protein, Human
  • Transcription Factors
ispartof: Proceedings of the National Academy of Sciences of the United States of America, July 19, 2011, Vol.108(29), pp.E314-E322
description: 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 Prep1i/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 Prep1i/i MEFs. In human fibroblasts, acute Prep1 down-regulation by siRNA induces DNA damage response, like in Prep1i/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 oncogene-induced senescence, and H-RasV¹²-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. ; p. E314-E322.
language: eng
source:
identifier: E-ISSN: 1091-6490 ; DOI: 10.1073/pnas.1105216108
fulltext: fulltext
issn:
  • 10916490
  • 1091-6490
url: Link


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titleHomeodomain transcription factor and tumor suppressor Prep1 is required to maintain genomic stability.
creatorIotti, Giorgio ; Longobardi, Elena ; Masella, Silvia ; Dardaei, Leila ; De Santis, Francesca ; Micali, Nicola ; Blasi, Francesco
contributorIotti, Giorgio (correspondence author) ; Iotti, Giorgio (record owner)
ispartofProceedings of the National Academy of Sciences of the United States of America, July 19, 2011, Vol.108(29), pp.E314-E322
identifierE-ISSN: 1091-6490 ; DOI: 10.1073/pnas.1105216108
subjectAnimals–Metabolism ; Cell Transformation, Neoplastic–Genetics ; Chromatin Immunoprecipitation–Cytology ; Comet Assay–Metabolism ; Cytogenetic Analysis–Genetics ; DNA Damage–Physiology ; Embryo, Mammalian–Physiology ; Fibroblasts–Genetics ; Gamma Rays–Radiation Effects ; Gene Expression Regulation–Metabolism ; Genomic Instability–Physiology ; Heterochromatin–Genetics ; Homeodomain Proteins–Metabolism ; Humans–Physiology ; Mice–Physiology ; Oligonucleotides–Physiology ; Transcription Factors–Physiology ; Heterochromatin ; Homeodomain Proteins ; Oligonucleotides ; Pknox1 Protein, Human ; Transcription Factors
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descriptionPrep1 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 Prep1i/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 Prep1i/i MEFs. In human fibroblasts, acute Prep1 down-regulation by siRNA induces DNA damage response, like in Prep1i/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 oncogene-induced senescence, and H-RasV¹²-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. ; p. E314-E322.
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titleHomeodomain transcription factor and tumor suppressor Prep1 is required to maintain genomic stability.
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titleHomeodomain transcription factor and tumor suppressor Prep1 is required to maintain genomic stability.
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