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HDMX regulates p53 activity and confers chemoresistance to 3-bis(2-chloroethyl)-1-nitrosourea.

Publication ,  Journal Article
Jin, G; Cook, S; Cui, B; Chen, WC; Keir, ST; Killela, P; Di, C; Payne, CA; Gregory, SG; McLendon, R; Bigner, DD; Yan, H
Published in: Neuro Oncol
September 2010

Glioblastoma multiforme (GBM) is one of the deadliest tumors afflicting humans, and the mechanisms of its onset and progression remain largely undefined. Our attempts to elucidate its molecular pathogenesis through DNA copy-number analysis by genome-wide digital karyotyping and single nucleotide polymorphism arrays identified a dramatic focal amplification on chromosome 1q32 in 4 of 57 GBM tumors. Quantitative real-time PCR measurements revealed that HDMX is the most commonly amplified and overexpressed gene in the 1q32 locus. Further genetic screening of 284 low- and high-grade gliomas revealed that HDMX amplifications occur solely in pediatric and adult GBMs and that they are mutually exclusive of TP53 mutations and MDM2 amplifications. Here, we demonstrate that HDMX regulates p53 to promote GBM growth and attenuates tumor response to chemotherapy. In GBM cells, HDMX overexpression inhibits p53-mediated transcriptional activation of p21, releases cells from G0 to G1 phase, and enhances cellular proliferation. HDMX overexpression does not affect the expression of PUMA and BAX proapoptotic genes. While in GBM cells treated with the chemotherapeutic agent 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), HDMX appears to stabilize p53 and promote phosphorylation of the DNA double-stranded break repair protein H2AX, up-regulate the DNA repair gene VPX, stimulate DNA repair, and confer resistance to BCNU. In summary, HDMX exhibits bona fide oncogenic properties and offers a promising molecular target for GBM therapeutic intervention.

Duke Scholars

Published In

Neuro Oncol

DOI

EISSN

1523-5866

Publication Date

September 2010

Volume

12

Issue

9

Start / End Page

956 / 966

Location

England

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Tumor Suppressor Protein p53
  • Transfection
  • Reverse Transcriptase Polymerase Chain Reaction
  • RNA, Small Interfering
  • Proto-Oncogene Proteins
  • Polymorphism, Single Nucleotide
  • Oncology & Carcinogenesis
  • Nuclear Proteins
  • Mice
 

Citation

APA
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ICMJE
MLA
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Jin, G., Cook, S., Cui, B., Chen, W. C., Keir, S. T., Killela, P., … Yan, H. (2010). HDMX regulates p53 activity and confers chemoresistance to 3-bis(2-chloroethyl)-1-nitrosourea. Neuro Oncol, 12(9), 956–966. https://doi.org/10.1093/neuonc/noq045
Jin, Genglin, Stephen Cook, Bo Cui, William C. Chen, Stephen T. Keir, Patrick Killela, Chunhui Di, et al. “HDMX regulates p53 activity and confers chemoresistance to 3-bis(2-chloroethyl)-1-nitrosourea.Neuro Oncol 12, no. 9 (September 2010): 956–66. https://doi.org/10.1093/neuonc/noq045.
Jin G, Cook S, Cui B, Chen WC, Keir ST, Killela P, et al. HDMX regulates p53 activity and confers chemoresistance to 3-bis(2-chloroethyl)-1-nitrosourea. Neuro Oncol. 2010 Sep;12(9):956–66.
Jin, Genglin, et al. “HDMX regulates p53 activity and confers chemoresistance to 3-bis(2-chloroethyl)-1-nitrosourea.Neuro Oncol, vol. 12, no. 9, Sept. 2010, pp. 956–66. Pubmed, doi:10.1093/neuonc/noq045.
Jin G, Cook S, Cui B, Chen WC, Keir ST, Killela P, Di C, Payne CA, Gregory SG, McLendon R, Bigner DD, Yan H. HDMX regulates p53 activity and confers chemoresistance to 3-bis(2-chloroethyl)-1-nitrosourea. Neuro Oncol. 2010 Sep;12(9):956–966.
Journal cover image

Published In

Neuro Oncol

DOI

EISSN

1523-5866

Publication Date

September 2010

Volume

12

Issue

9

Start / End Page

956 / 966

Location

England

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Tumor Suppressor Protein p53
  • Transfection
  • Reverse Transcriptase Polymerase Chain Reaction
  • RNA, Small Interfering
  • Proto-Oncogene Proteins
  • Polymorphism, Single Nucleotide
  • Oncology & Carcinogenesis
  • Nuclear Proteins
  • Mice