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

Mol. Cell. Biol., 1 November 2002
Vol. 22, Issue 21, p. 7385-7397
DOI: 10.1128/MCB.22.21.7385-7397.2002

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

  1. Jennifer A. Benanti1,2,
  2. Dawnnica K. Williams1,2,
  3. Kristin L. Robinson1,
  4. Harvey L. Ozer3 and
  5. Denise A. Galloway1,*
  1. 1Program in Cancer Biology, Fred Hutchinson Cancer Research Center
  2. 2Molecular and Cellular Biology Graduate Program, University of Washington, and Fred Hutchinson Cancer Research Center, Seattle, Washington
  3. 3Department of Microbiology and Molecular Genetics, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark, New Jersey

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.

FOOTNOTES

    • Received 12 March 2002.
    • Returned for modification 13 May 2002.
    • Accepted 11 July 2002.
  • *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.

Citation:

J. A. Benanti, D. K. Williams, K. L. Robinson, H. L. Ozer, and D. A. Galloway, Induction of Extracellular Matrix-Remodeling Genes by the Senescence-Associated Protein APA-1. Mol. Cell. Biol. 22, 7385-7397 (2002).

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