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Mol. Cell. Biol. 22 (21): 7385-7397

Copyright © 2002 by the American Society for Microbiology. All rights reserved.

Induction of Extracellular Matrix-Remodeling Genes by the Senescence-Associated Protein APA-1

Jennifer A. Benanti,1,2 Dawnnica K. Williams,1,2 Kristin L. Robinson,1 Harvey L. Ozer,3 and Denise A. Galloway1*

Program in Cancer Biology, Fred Hutchinson Cancer Research Center,1 Molecular and Cellular Biology Graduate Program, University of Washington, and Fred Hutchinson Cancer Research Center, Seattle, Washington,2 Department of Microbiology and Molecular Genetics, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark, New Jersey3

Received for publication 12 March 2002. Revision received 13 May 2002. Accepted for publication 11 July 2002.

Abstract: Human fibroblasts undergo cellular senescence after a finite number of divisions, in response to the erosion of telomeres. In addition to being terminally arrested in the cell cycle, senescent fibroblasts express genes that are normally induced upon wounding, including genes that remodel the extracellular matrix. We have identified the novel zinc finger protein APA-1, whose expression increased in senescent human fibroblasts independent of telomere shortening. Extended passage, telomerase-immortalized fibroblasts had increased levels of APA-1 as well as the cyclin-dependent kinase inhibitor p16. In fibroblasts, APA-1 was modified by the ubiquitin-like protein SUMO-1, which increased APA-1 half-life, possibly by blocking ubiquitin-mediated degradation. Overexpression of APA-1 did not cause cell cycle arrest; but, it induced transcription of the extracellular matrix-remodeling genes MMP1 and PAI2, which are associated with fibroblast senescence. MMP1 and PAI2 transcript levels also increased in telomerase-immortalized fibroblasts that had high levels of APA-1, demonstrating that the matrix-remodeling phenotype of senescent fibroblasts was not induced by telomere attrition alone. APA-1 was able to transactivate and bind to the MMP1 promoter, suggesting that APA-1 is a transcription factor that regulates expression of matrix-remodeling genes during fibroblast senescence.

* Corresponding author. Mailing address: Program in Cancer Biology, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. N., C1-015, Seattle, WA 98109-1024. Phone: (206) 667-4500. Fax: (206) 667-5815. E-mail: dgallowa{at}fhcrc.org.

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