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Ku proteins interact with activator protein-2 transcription factors and contribute to ERBB2 overexpression in breast cancer cell lines
Breast Cancer Research, 11/23/09

Nolens G et al. – Ku proteins in interaction with AP-2 (alpha and gamma) contribute to increased ERBB2 mRNA and protein levels in breast cancer cells.

• Ku proteins identified as AP-2 alpha interacting proteins by glutathione serine transferase (GST)-pull down followed by mass spectrometry
• Transfection of cells with siRNA, expression vectors and reporter vectors as well as chromatin immunoprecipitation (ChIP) assay used to ascertain implication of Ku proteins on ERBB2 expression

• Nuclear proteins from BT-474 cells overexpressing AP-2 alpha and AP-2 gamma incubated with GST-AP2 or GST coated beads
• Among proteins retained specifically on GST-AP2 coated beads Ku70 and Ku80 proteins identified by mass spectrometry
• Contribution of Ku proteins to ERBB2 gene expression in BT-474 and SKBR3 cell lines investigated by downregulating Ku proteins through use of specific siRNAs
• Depletion of Ku proteins led to downregulation of ERBB2 mRNA and protein levels
• Reduction of Ku80 in HCT116 cell line decreased AP-2 alpha activity on reporter vector containing AP-2 binding site linked to ERBB2 core promoter, and transfection of Ku80 increased activity of AP-2 alpha on promoter
• Ku siRNAs inhibited activity of reporter vector in BT-474 and SKBR3 cell lines and activity of ERBB2 promoter further reduced by combining Ku siRNAs with AP-2 alpha and AP-2 gamma siRNAs
• ChIP experiments with chromatin extracted from wild type or AP-2 alpha and AP-2 gamma or Ku70 siRNA transfected BT-474 cells demonstrated Ku70 recruitment to the ERBB2 proximal promoter in association with AP-2 alpha and AP-2 gamma
• Ku70 siRNA like AP-2 siRNAs, greatly reduced PolII recruitment to ERBB2 proximal promoter

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