Regulated ATF5 loss-of-function in adult mice blocks formation and causes regression/eradication of gliomas

A. Arias, M. W. Lamé, L. Santarelli, R. Hen, L. A. Greene, James M Angelastro

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

Glioblastomas are among the most incurable cancers. Our past findings indicated that glioblastoma cells, but not neurons or glia, require the transcription factor ATF5 (activating transcription factor 5) for survival. However, it was unknown whether interference with ATF5 function can prevent or promote regression/eradication of malignant gliomas in vivo. To address this issue, we created a mouse model by crossing a human glial fibrillary acidic protein (GFAP) promoter-tetracycline transactivator mouse line with tetracycline operon-dominant negative-ATF5 (d/n-ATF5) mice to establish bi-transgenic mice. In this model, d/n-ATF5 expression is controlled by doxycycline and the promoter for GFAP, a marker for stem/progenitor cells as well as gliomas. Endogenous gliomas were produced with high efficiency by retroviral delivery of platelet-derived growth factor (PDGF)-B and p53-short hairpin RNA (shRNA) in adult bi-transgenic mice in which expression of d/n-ATF5 was spatially and temporally regulated. Induction of d/n-ATF5 before delivery of PDGF-B/p53-shRNA virus greatly reduced the proportion of mice that formed tumors. Moreover, d/n-ATF5 induction after tumor formation led to regression/eradication of detectable gliomas without evident damage to normal brain cells in all 24 mice assessed.

Original languageEnglish (US)
Pages (from-to)739-751
Number of pages13
JournalOncogene
Volume31
Issue number6
DOIs
StatePublished - Feb 2012

Fingerprint

Activating Transcription Factors
Glioma
Proto-Oncogene Proteins c-sis
Glial Fibrillary Acidic Protein
Glioblastoma
Tetracycline
Small Interfering RNA
Transgenic Mice
Stem Cells
Neoplasms
Trans-Activators
Doxycycline
RNA Viruses
Operon
Neuroglia
Transcription Factors
Neurons
Survival
Brain

Keywords

  • ATF5
  • glioma
  • PDGF-B
  • tumorigenesis

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Regulated ATF5 loss-of-function in adult mice blocks formation and causes regression/eradication of gliomas. / Arias, A.; Lamé, M. W.; Santarelli, L.; Hen, R.; Greene, L. A.; Angelastro, James M.

In: Oncogene, Vol. 31, No. 6, 02.2012, p. 739-751.

Research output: Contribution to journalArticle

Arias, A. ; Lamé, M. W. ; Santarelli, L. ; Hen, R. ; Greene, L. A. ; Angelastro, James M. / Regulated ATF5 loss-of-function in adult mice blocks formation and causes regression/eradication of gliomas. In: Oncogene. 2012 ; Vol. 31, No. 6. pp. 739-751.
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