Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

Logo for

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.



THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Condensin complexes regulate mitotic progression and interphase chromatin structure in embryonic stem cells.
T. G. Fazzio and B. Panning (2010)
J. Cell Biol. 188, 491-503
   Abstract »    Full Text »    PDF »
Epigenetic Down-Regulation of ARF Expression Is a Selection Step in Immortalization of Human Fibroblasts by c-Myc.
J. A. Benanti, M. L. Wang, H. E. Myers, K. L. Robinson, C. Grandori, and D. A. Galloway (2007)
Mol. Cancer Res. 5, 1181-1189
   Abstract »    Full Text »    PDF »
GeneChip, geNorm, and gastrointestinal tumors: novel reference genes for real-time PCR.
M. Kidd, B. Nadler, S. Mane, G. Eick, M. Malfertheiner, M. Champaneria, R. Pfragner, and I. Modlin (2007)
Physiol Genomics 30, 363-370
   Abstract »    Full Text »    PDF »
The HBP1 Transcriptional Repressor Participates in RAS-Induced Premature Senescence.
X. Zhang, J. Kim, R. Ruthazer, M. A. McDevitt, D. E. Wazer, K. E. Paulson, and A. S. Yee (2006)
Mol. Cell. Biol. 26, 8252-8266
   Abstract »    Full Text »    PDF »
Fibromodulin Gene Transcription Is Induced by Ultraviolet Irradiation, and Its Regulation Is Impaired in Senescent Human Fibroblasts.
M. A. Bevilacqua, B. Iovine, N. Zambrano, C. D'Ambrosio, A. Scaloni, T. Russo, and F. Cimino (2005)
J. Biol. Chem. 280, 31809-31817
   Abstract »    Full Text »    PDF »
Large-Scale Profiling of Rab GTPase Trafficking Networks: The Membrome.
C. Gurkan, H. Lapp, C. Alory, A. I. Su, J. B. Hogenesch, and W. E. Balch (2005)
Mol. Biol. Cell 16, 3847-3864
   Abstract »    Full Text »    PDF »
Normal Human Fibroblasts Are Resistant to RAS-Induced Senescence.
J. A. Benanti and D. A. Galloway (2004)
Mol. Cell. Biol. 24, 2842-2852
   Abstract »    Full Text »    PDF »
S-Adenosylmethionine Decarboxylase Degradation by the 26 S Proteasome Is Accelerated by Substrate-mediated Transamination.
A. Yerlikaya and B. A. Stanley (2004)
J. Biol. Chem. 279, 12469-12478
   Abstract »    Full Text »    PDF »
Cell senescence and hypermitogenic arrest.
M. V. Blagosklonny (2003)
EMBO Rep. 4, 358-362
   Abstract »    Full Text »    PDF »

To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882