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AP2 inhibits cancer cell growth and activates p21WAF1/CIP1 expression

Nature Genetics volume 15, pages 7882 (1997) | Download Citation

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Abstract

The 52-kD Activator Protein (AP2) is a DMA-binding transcription factor1–3 implicated in signalling terminal differentiation2–4. Profound developmental abnormalities have been recently observed in AP2-null mice5,6. The molecular events by which AP2 promotes differentiation or development are, however, unknown. Increased expression of the universal cell cycle inhibitor P21WAF1/CIP1 occurs in growth-arrested terminally differentiating cells7–12. In a search for cellular factors that could activate p21 during phorbol ester (TPA)-induced differentiation, we identified AP2 as a regulator of p21 expression. Mutagenesis of an AP2 DMA-binding site within a p21 promoter-luciferase reporter inhibited its activation by either AP2 transfection or TPA stimulation. Endogenous p21 protein levels were elevated and DMA synthesis was inhibited in AP2 versus control vector-transfected cells. Overexpression of AP2 in HepG2 human hepatoblastoma and SW480 human colon adenocarcinoma cells inhibited cell division and stable colony formation. These results link the differentiation-associated factor AP2 to negative cell cycle and growth control, possibly through p21 activation.

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Affiliations

  1. Howard Hughes Medical Institute, Laboratory of Molecular Oncology and Cell Cycle Regulation, Department of Medicine and Genetics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.

    • Yi-Xin Zeng
    • , Kumaravel Somasundaram
    •  & Wafik S. El-Deiry
  2. All correspondence should be addressed to W.S.E.-D.

    • Wafik S. El-Deiry

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DOI

https://doi.org/10.1038/ng0197-78

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