Sci. Aging Knowl. Environ., 2 July 2003
Vol. 2003, Issue 26, p. nw92
[DOI: 10.1126/sageke.2003.26.nw92]

NOTEWORTHY ARTICLES

Trashing a Longevity-Slasher

p53 partner disposes of a protein that promotes aging

R. John Davenport

http://sageke.sciencemag.org/cgi/content/full/sageke;2003/26/nw92

Key Words: tumor suppressor • post-transcriptional regulation • ubiquitin • proteasome

A protein that dooms a cancer-prevention molecule also sends one that curtails longevity to its destruction, according to new research. The cell culture study reveals an unexpected strategy for regulating a signaling pathway that influences life span. Understanding how that tactic influences aging in animals awaits further study.

Blocking the worm, fly, and rodent versions of the insulin-like growth factor-1 (IGF-1) signaling pathway retards aging (see "One for All"). Scientists want to know what regulates the pathway. Cancer researcher Olle Larsson and colleagues at the Karolinska Institute in Stockholm, Sweden, previously observed that boosting amounts of a cancer-quelling protein called p53 raises quantities of IGF-1R, a protein that conveys IGF-1's signal. However, other work had revealed that p53 subdues the IGF-1 pathway by quieting the gene that produces IGF-1R. The researchers decided to delve deeper into the mechanisms that govern IGF-1R quantities in cells.

They knew that another protein called Mdm2 marks excess p53 for disposal; they wondered whether Mdm2 does the same to IGF-1R. The team isolated IGF-1R from human skin cells and found that the molecule carries the disposal tag. Blocking production of Mdm2 reduced the number of IGF-1R molecules bearing the tag, suggesting that Mdm2 helps attach it to IGF-1R. Additional experiments revealed that Mdm2 and IGF-1R stick together in cells, further supporting that idea.

Next, the researchers blocked production of p53, Mdm2, or both in the cells, then measured how quickly IGF-1R disappeared. When they suppressed p53, IGF-1R quantities dwindled more rapidly than when they muffled Mdm2 alone or p53 and Mdm2 together. The results suggest that Mdm2 is necessary for efficient IGF-1R incineration and that p53 blocks the demolition. p53 normally binds Mdm2 in a cell's nucleus; the authors propose that when p53 concentrations fall, Mdm2 ambles into the cytoplasm, where it can target IGF-1R. Excess p53 accelerates aging, according to recent studies (see Campisi Perspective and "Tumor-Free, But Not in the Clear"). The new finding fits well with that idea, says Larsson. Large amounts of p53 sop up Mdm2 and prevent it from depleting IGF-1R, he speculates; continued IGF-1 signaling promotes aging.

Although the results don't resolve the paradoxical observations about p53's relation to IGF-1R, they unveil an unforeseen method by which the body might govern IGF-1R quantities. Regulation by Mdm2 "is a completely new idea," says oncologist Norman ("Ned") Sharpless of the University of North Carolina, Chapel Hill. If confirmed, the finding will interest researchers who study aging, given that defects in the IGF-1 pathway prolong life span, he says. Because the regulatory network is complex, predicting how Mdm2 influences longevity is difficult, he cautions. Molecular biologist Judith Campisi of University of California, Berkeley, concurs. p53 cranks up production of Mdm2, she points out, which would lower IGF-1R concentrations; the resulting decrease in IGF-1 signaling should slow, rather than speed, aging. Nevertheless, previous studies suggested that Mdm2 primarily regulates p53; the new study shows that "it regulates more than p53 and that IGF-1R is potentially an important target," says Campisi. Further clarifying these relationships might help researchers figure out ways to annihilate aging.

--R. John Davenport


July 2, 2003
  1. L. Girnita, A. Girnita, O. Larsson, Mdm2-dependent ubiquitination and degradation of the insulin-like growth factor 1 receptor. Proc. Natl. Acad. Sci. U.S.A., 23 June 2003 [e-pub ahead of print]. [Abstract] [Full Text]
Citation: R. J. Davenport, Trashing a Longevity-Slasher. Sci. SAGE KE 2003, nw92 (2 July 2003)
http://sageke.sciencemag.org/cgi/content/full/sageke;2003/26/nw92








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