ZNF217 suppresses cell death associated with chemotherapy and telomere dysfunction

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

Research output: Contribution to journalArticle

50 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)3219-3225
Number of pages7
JournalHuman molecular genetics
Volume14
Issue number21
DOIs
StatePublished - Nov 1 2005
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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  • Cite this

    Huang, G., Krig, S., Kowbel, D., Xu, H., Hyun, B., Volik, S., Feuerstein, B., Mills, G. B., Stokoe, D., Yaswen, P., & Collins, C. (2005). ZNF217 suppresses cell death associated with chemotherapy and telomere dysfunction. Human molecular genetics, 14(21), 3219-3225. https://doi.org/10.1093/hmg/ddi352