Dominant negative interference of transcription factor AP-2 causes inhibition of ErbB-3 expression and suppresses malignant cell growth.
ErbB-3 (HER3) is a member of the epidermal growth factor receptor family. Increasing evidence suggests that elevated expression of ErbB-3 is important for malignancy. In this study, we found that elevated levels of ErbB-3 expression did not occur in the absence of AP-2gamma in a panel of human mammary epithelial and fibroblasts cell lines. In contrast, there was no association between the expression of AP-2alpha or AP-2beta and the level of ErbB-3, or between AP-2alpha and AP-2gamma double positivity and ErbB-3 expression. In co-transfection experiments, exogenous expression of AP-2gamma robustly activated ErbB-3 promoter activity. Moreover, expression of a dominant negative AP-2 protein, AP-2delta (deleted residues 31-117), not only repressed the ErbB-3 promoter activity but also suppressed endogenous ErbB-3 transcription in the ErbB-3 overexpressing cell line MRC-5VA. Overexpression of AP-2A resulted in a decreased proliferation rate and inhibitin of colony formation. Taken together, these data strongly support a role for the AP-2 gene family, in particular, AP-2gamma, in the control of ErbB-3 expression. Interference with the function of transcription factor AP-2 might provide a potential strategy for modulation of the malignant phenotype.
Zhu
Chun-Hong
CH
Free Radical & Radiation Biology Program, Department of Radiation Oncology, and Holden Comprehensive Cancer Center, The University of Iowa, Iowa City 52242, USA.
Domann
Frederick E
FE
D001940:Breast / Q000166:cytology / Q000473:pathology*; D001943:Breast Neoplasms / Q000235:genetics* / Q000503:physiopathology; D002455:Cell Division; D002471:Cell Transformation, Neoplastic; D004268:DNA-Binding Proteins / Q000494:pharmacology*; D005260:Female; D005347:Fibroblasts / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic; D018815:Genes, erbB; D006801:Humans; D008168:Lung / Q000166:cytology; D010641:Phenotype; D020893:Receptor, ErbB-3 / Q000096:biosynthesis*; D050656:Transcription Factor AP-2; D014157:Transcription Factors / Q000494:pharmacology*
D004268:DNA-Binding Proteins; C493673:TFAP2A protein, human; C493677:TFAP2B protein, human; C493679:TFAP2C protein, human; D050656:Transcription Factor AP-2; D014157:Transcription Factors; D020893:Receptor, ErbB-3