Human Molecular Genetics Advance Access originally published online on October 3, 2005
Human Molecular Genetics 2005 14(21):3219-3225; doi:10.1093/hmg/ddi352
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ZNF217 suppresses cell death associated with chemotherapy and telomere dysfunction
1Cancer Research Institute and 2Brain Tumor Research Center of the Department of Neurological Surgery, The University of California San Francisco, San Francisco, CA 94143-0808, USA, 3Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA and 4Department of Molecular Therapeutics, University of Texas MD, Anderson Cancer Center, Houston, TX, USA
* To whom correspondence should be addressed. Tel: +1 4155027065; Fax: +1 4154768218; Email: collins{at}cc.ucsf.edu
Received July 24, 2005; Accepted September 16, 2005
Chromosome 20q13.2 is amplified in 20–30% of early-stage breast tumors and is associated with poor prognosis. Detailed mapping of the amplified region using molecular cytogenetics, positional cloning and genomic sequencing culminated in a detailed molecular description of the candidate oncogene ZNF217. ZNF217 proteins resemble Kruppel-like transcription factors, localize predominately to the nucleus and associate with proteins involved in transcriptional repression. The findings that ZNF217 can immortalize human mammary epithelial cells and that its amplification is associated with poor prognosis suggest that it may play roles in both early- and late-stage breast cancer. We present evidence that ZNF217 can attenuate apoptotic signals resulting from telomere dysfunction as well as from doxorubicin-induced DNA damage and that silencing ZNF217 with siRNA restores sensitivity to doxorubicin. Moreover, elevated ZNF217 leads to increased phosphorylation of Akt, whereas inhibition of the phosphatidylinositol 3 kinase pathway and Akt phosphorylation decreases ZNF217 protein levels and increases sensitivity to doxorubicin. These results suggest that ZNF217 may promote neoplastic transformation by increasing cell survival during telomeric crisis and may promote later stages of malignancy by increasing cell survival during chemotherapy.
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