Genomically amplified Akt3 activates DNA repair pathway and promotes glioma progression

Kristen M. Turner, Youting Sun, Ping Ji, Kirsi J. Granberg, Brady Bernard, Limei Hu, David E. Cogdell, Xinhui Zhou, Olli Yli-Harja, Matti Nykter, Ilya Shmulevich, W. K Alfred Yung, Gregory N. Fuller, Wei Zhang

Research output: Contribution to journalArticle

42 Citations (Scopus)

Abstract

Akt is a robust oncogene that plays key roles in the development and progression of many cancers, including glioma. We evaluated the differential propensities of the Akt isoforms toward progression in the well-characterized RCAS/Ntv-a mouse model of PDGFB-driven low grade glioma. A constitutively active myristoylated form of Akt1 did not induce high-grade glioma (HGG). In stark contrast, Akt2 and Akt3 showed strong progression potential with 78% and 97% of tumors diagnosed as HGG, respectively. We further revealed that significant variations in polarity and hydropathy values among the Akt isoforms in both the pleckstrin homology domain (P domain) and regulatory domain (R domain) were critical in mediating glioma progression. Gene expression profiles from representative Akt-derived tumors indicated dominant and distinct roles for Akt3, consisting primarily of DNA repair pathways. TCGA data from human GBM closely reflected the DNA repair function, as Akt3 was significantly correlated with a 76-gene signature DNA repair panel. Consistently, compared with Akt1 and Akt2 overexpression models, Akt3-expressing human GBM cells had enhanced activation of DNA repair proteins, leading to increased DNA repair and subsequent resistance to radiation and temozolomide. Given the wide range of Akt3-amplified cancers, Akt3 may represent a key resistance factor.

Original languageEnglish (US)
Pages (from-to)3421-3426
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number11
DOIs
StatePublished - Mar 17 2015
Externally publishedYes

Fingerprint

Glioma
DNA Repair
temozolomide
Neoplasms
Protein Isoforms
Proto-Oncogene Proteins c-sis
R Factors
Oncogenes
Transcriptome
Radiation
Genes
Proteins

Keywords

  • Akt
  • DNA repair
  • Glioma
  • RCAS/tv-a mouse model

ASJC Scopus subject areas

  • General

Cite this

Genomically amplified Akt3 activates DNA repair pathway and promotes glioma progression. / Turner, Kristen M.; Sun, Youting; Ji, Ping; Granberg, Kirsi J.; Bernard, Brady; Hu, Limei; Cogdell, David E.; Zhou, Xinhui; Yli-Harja, Olli; Nykter, Matti; Shmulevich, Ilya; Yung, W. K Alfred; Fuller, Gregory N.; Zhang, Wei.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 112, No. 11, 17.03.2015, p. 3421-3426.

Research output: Contribution to journalArticle

Turner, KM, Sun, Y, Ji, P, Granberg, KJ, Bernard, B, Hu, L, Cogdell, DE, Zhou, X, Yli-Harja, O, Nykter, M, Shmulevich, I, Yung, WKA, Fuller, GN & Zhang, W 2015, 'Genomically amplified Akt3 activates DNA repair pathway and promotes glioma progression', Proceedings of the National Academy of Sciences of the United States of America, vol. 112, no. 11, pp. 3421-3426. https://doi.org/10.1073/pnas.1414573112
Turner, Kristen M. ; Sun, Youting ; Ji, Ping ; Granberg, Kirsi J. ; Bernard, Brady ; Hu, Limei ; Cogdell, David E. ; Zhou, Xinhui ; Yli-Harja, Olli ; Nykter, Matti ; Shmulevich, Ilya ; Yung, W. K Alfred ; Fuller, Gregory N. ; Zhang, Wei. / Genomically amplified Akt3 activates DNA repair pathway and promotes glioma progression. In: Proceedings of the National Academy of Sciences of the United States of America. 2015 ; Vol. 112, No. 11. pp. 3421-3426.
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