Tissue-Tampering Turn-On
Authors: Davenport R. John 
Published: August 2003

Senescent cells are silent but deadly: They've stopped dividing, yet they disperse proteins that destroy tissues and spur cancer. New work unveils a protein that apparently sparks this explosion of noxious molecules. The study is the first to identify a molecule that directly activates genes associated with senescence and could lead researchers to other important regulators.
Certain types of cells growing in culture dishes eventually shudder to a halt, coming to rest in a state known as senescence. Whether senescence occurs in organisms is unclear, but some researchers think that the process could divert renegade cells from a cancerous path by sending them into permanent slumber. But like people who've eaten too many beans, senescent cells can agitate others in close proximity, because they activate genes and emit the resulting poisonous products into surrounding tissue. These molecules include inflammation- and growth-stimulating proteins, as well as enzymes that chew up extracellular matrix (ECM), the scaffold that glues cells together. As a result, senescent cells might contribute to aging or age-related disease by inflaming and degrading tissue, and they can even prompt nearby cells to reproduce uncontrollably. Although scientists know that senescence turns some genes on and some off, they haven't identified the key regulatory molecules.
In the new work, Benanti and colleagues looked for molecular laborers that might work alongside ARF, a protein cells need to senesce. The researchers netted a protein called APA-1 that binds to ARF. Experiments with cultured connective tissue cells showed that cells produce more and more APA-1 as they age. Cells that senesce early because they make extra ARF also generate more APA-1 than normal, hinting at a role for APA-1 in senescence. Additional studies revealed that APA-1 activates genes whose protein products chop up ECM: The concentration of messenger RNA from these genes increased in cells that produced copious amounts of APA-1, and APA-1 binds to DNA sequences that stimulate production of the matrix-hewing enzymes.
Cells with extra APA-1 don't stop dividing earlier than control cells do, however, indicating that the gene activator by itself doesn't trigger senescence. Instead, APA-1 might require other senescence signals to function, the researchers posit. To test whether one such signal stimulates APA-1, the team investigated whether the shortening of telomeres, DNA-protein caps that protect the ends of chromosomes, is necessary for APA-1's effect. They maintained long telomeres in cells by producing the enzyme telomerase and found that amounts of APA-1 still rose with age. Additional research is needed to identify the senescence signals to which the protein responds.
Although scientists have identified a number of proteins that regulate entry into senescence, this is the first time that they have directly linked an activator protein to senescence-associated changes in gene activity, says cancer biologist David Cobrinik of Columbia University in New York City. Further studies of APA-1 might reveal the proteins that promote its activity and initiate senescence. The answers could help researchers figure out what makes senescent cells such stinkers.
--R. John Davenport

J. A. Benanti, D. K. Williams, K. L. Robinson, H. L. Ozer, 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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