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CHEK2 genomic and proteomic analyses reveal genetic inactivation or endogenous activation across the 60 cell lines of the US National Cancer Institute

  1. Author:
    Zoppoli, G.
    Solier, S.
    Reinhold, W. C.
    Liu, H.
    Connelly, J. W.
    Monks, A.
    Shoemaker, R. H.
    Abaan, O. D.
    Davis, S. R.
    Meltzer, P. S.
    Doroshow, J. H.
    Pommier, Y.

  2. Author Address

    [Zoppoli, G.] Univ Genoa, Dept Internal Med DiMI, I-16132 Genoa, Italy. [Zoppoli, G.; Solier, S.; Reinhold, W. C.; Liu, H.; Doroshow, J. H.; Pommier, Y.] NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Liu, H.] Mayo Clin, Div Biomed Stat & Informat, Rochester, MN USA. [Connelly, J. W., Jr.; Monks, A.] SAIC Frederick Inc, Lab Funct Genom, NCI Frederick, Frederick, MD USA. [Shoemaker, R. H.] NCI, Screening Technol Branch, Dev Therapeut Program, Div Canc Treatment & Diag,NIH, Frederick, MD 21701 USA. [Abaan, O. D.; Davis, S. R.; Meltzer, P. S.] NCI, Genet Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Doroshow, J. H.] NCI, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA.;Zoppoli, G (reprint author), Univ Genoa, Dept Internal Med DiMI, Avancorpo 2 Piano,Vle Benedetto XV,Room 223,6, I-16132 Genoa, Italy;gabriele.zoppoli@unige.it pommier@nih.gov
    1. Year: 2012
    2. Date: Jan
  2. Journal: Oncogene
    1. 31
    2. 4
    3. Pages: 403-418
  4. Type of Article: Article
  5. ISSN: 0950-9232
  1. Abstract:

    CHEK2 encodes a serine/threonine kinase (Chk2) activated by ATM in response to DNA double-strand breaks. On the one hand, CHEK2 has been described as a tumor suppressor with proapoptotic, cell-cycle checkpoint and mitotic functions. On the other hand, Chk2 is also commonly activated (phosphorylated at T68) in cancers and precancerous lesions. Here, we report an extensive characterization of CHEK2 across the panel of 60 established cancer cell lines from the NCI Anticancer Screen (the NCI-60) using genomic and proteomic analyses, including exon-specific mRNA expression, DNA copy-number variation (CNV) by aCGH, exome sequencing, as well as western blot analyses for total and activated (pT68-Chk2) Chk2. We show that the high heterogeneity of Chk2 levels in cancer cells is primarily due to its inactivation (owing to low gene expression, alternative splicing, point mutations, copy-number alterations and premature truncation) or reduction of protein levels. Moreover, we observe that a significant percentage of cancer cells (12% of the NCI-60 and HeLa cells) show high endogenous Chk2 activation, which is always associated with p53 inactivation, and which is accompanied by downregulation of the Fanconi anemia and homologous recombination pathways. We also report the presence of activated Chk2 (pT68-Chk2) along with histone gamma-H2AX in centrosomes. Oncogene (2012) 31, 403-418; doi: 10.1038/onc.2011.283; published online 18 July 2011

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  2. DOI: 10.1038/onc.2011.283
  3. View record in Web of Science®
  4. WOS: 000300219300001

Library Notes

  1. Fiscal Year: FY2011-2012
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