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Genomically amplified Akt3 activates DNA repair pathway and promotes glioma progression

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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 journalArticleScientificpeer-review

Harvard

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

APA

Turner, K. M., Sun, Y., Ji, P., Granberg, K. J., Bernard, B., Hu, L., ... 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, 112(11), 3421-3426. https://doi.org/10.1073/pnas.1414573112

Vancouver

Turner KM, Sun Y, Ji P, Granberg KJ, Bernard B, Hu L et al. Genomically amplified Akt3 activates DNA repair pathway and promotes glioma progression. Proceedings of the National Academy of Sciences of the United States of America. 2015 Mar 17;112(11):3421-3426. https://doi.org/10.1073/pnas.1414573112

Author

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.

Bibtex - Download

@article{9ce94c2f9af04b33b1060a4a1c3fcb3a,
title = "Genomically amplified Akt3 activates DNA repair pathway and promotes glioma progression",
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.",
keywords = "Akt, DNA repair, Glioma, RCAS/tv-a mouse model",
author = "Turner, {Kristen M.} and Youting Sun and Ping Ji and Granberg, {Kirsi J.} and Brady Bernard and Limei Hu and Cogdell, {David E.} and Xinhui Zhou and Olli Yli-Harja and Matti Nykter and Ilya Shmulevich and Yung, {W. K Alfred} and Fuller, {Gregory N.} and Wei Zhang",
note = "EXT={"}Zhang, Wei{"}",
year = "2015",
month = "3",
day = "17",
doi = "10.1073/pnas.1414573112",
language = "English",
volume = "112",
pages = "3421--3426",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "National Academy of Sciences",
number = "11",

}

RIS (suitable for import to EndNote) - Download

TY - JOUR

T1 - Genomically amplified Akt3 activates DNA repair pathway and promotes glioma progression

AU - Turner, Kristen M.

AU - Sun, Youting

AU - Ji, Ping

AU - Granberg, Kirsi J.

AU - Bernard, Brady

AU - Hu, Limei

AU - Cogdell, David E.

AU - Zhou, Xinhui

AU - Yli-Harja, Olli

AU - Nykter, Matti

AU - Shmulevich, Ilya

AU - Yung, W. K Alfred

AU - Fuller, Gregory N.

AU - Zhang, Wei

N1 - EXT="Zhang, Wei"

PY - 2015/3/17

Y1 - 2015/3/17

N2 - 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.

AB - 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.

KW - Akt

KW - DNA repair

KW - Glioma

KW - RCAS/tv-a mouse model

U2 - 10.1073/pnas.1414573112

DO - 10.1073/pnas.1414573112

M3 - Article

VL - 112

SP - 3421

EP - 3426

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 11

ER -