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Human Molecular Genetics Advance Access published online on October 3, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi352
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© The Author 2005. Published by Oxford University Press. All rights reserved
Received July 24, 2005
Revised September 16, 2005
Accepted September 16, 2005

Article

ZNF217 Suppresses Cell Death Associated with Chemotherapy and Telomere Dysfunction

Guiqing Huang 1, Sheryl Krig 2, David Kowbel 1, Hongmei Xu 1, Bill Hyun 1, Stas Volik 1, Burt Feuerstein 3, Gordon B. Mills 4, David Stokoe 1, Paul Yaswen 2, and Colin Collins 1*

1 The University of California San Francisco Cancer Center, San Francisco, California 94143-0808, USA
2 Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA
3 Brain Tumor Research Center of the Department of Neurological Surgery, The University Of California San Francisco, San Francisco, California, 94143-0808, USA
4 Department of Molecular Therapeutics, University of Texas M.D, Anderson Cancer Center, Houston

* To whom correspondence should be addressed.
Colin Collins, E-mail: Collins{at}cc.ucsf.edu


  Abstract

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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