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J. Biol. Chem., Vol. 277, Issue 8, 6637-6644, February 22, 2002

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A Subtractive Gene Expression Screen Suggests a Role of Transcription Factor AP-2 in Control of Proliferation and Differentiation^*

Petra Pfisterer, Julia Ehlermann^§, Martin Hegen, and Hubert Schorle^§¶

From the  Forschungszentrum Karlsruhe, ITG, Hermann von Helmholtz Platz 1, 76344 Eggenstein-Leopoldshafen and the ^§ Department of Developmental Pathology, Institute of Pathology, Bonn University, Sigmund-Freud Strasse 25, 53127 Bonn, Germany

The transcription factor AP-2 has been implicated as a cell type-specific regulator of gene expression during vertebrate embryogenesis based on its expression pattern in neural crest cells, ectoderm, and the nervous system in mouse and frog embryos. AP-2 is prominently expressed in cranial neural crest cells, a population of cells that migrate from the lateral margins of the brain plate during closure of the neural tube at day 8-9 of embryonic development. Homozygous AP-2 mutant mice die perinatally with cranio-abdominoschisis, full facial clefting, and defects in cranial ganglia and sensory organs, indicating the importance of this gene for proper development. By using a subtractive cloning approach, we identified a set of genes repressed by AP-2 that are described to retard cellular proliferation and induce differentiation and apoptosis. We show that these target genes are prematurely expressed in AP-2 mutant mice. One of the genes isolated, the Krüppel-box transcription factor KLF-4 implicated in induction of terminal differentiation and growth regulation, is found expressed in mutant embryonic fibroblasts. We show that fibroblasts lacking AP-2 display retarded growth but no enhanced apoptosis. Based on these data we suggest that AP-2 might be required for cell proliferation by suppression of genes inducing terminal differentiation, apoptosis, and growth retardation.

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