Sci. Aging Knowl. Environ., 21 May 2003
Old Livers Get a Complex
Newly discovered protein mélange might prevent old livers from regrowing
R. John Davenporthttp://sageke.sciencemag.org/cgi/content/full/sageke;2003/20/nw73
Key Words: E2F transcription factor partial hepatectomy hepatocyte
Like some people, elderly liver cells get stuck in their ways. A new study might reveal why: A protein that shackles liver growth gains new partners in old age, and the group of molecules blocks genes that spur growth. The results might explain why livers from old animals lose their ability to regenerate.
Remove half of a young animal's liver and it will bounce back to full size, because dormant liver cells revive and divide to fill in the missing tissue. But older beasts lose this capacity. Previous studies revealed that a protein called C/EBP prevents liver cells from duplicating. After part of a young animal's liver is removed, C/EBP disappears and cells flourish, although the signals that trigger this event are unknown. In older animals, however, C/EBP concentrations remain high after liver surgery. Molecular biologist Nikolai Timchenko of Baylor College of Medicine in Houston, Texas, and colleagues had previously found that in cells from intact young livers, C/EBP binds to and hogties so-called Cdk proteins, which otherwise spur growth by activating other proteins. The researchers wondered whether C/EBP functions similarly in old liver cells.
C/EBP did not bind to Cdks in liver cells from old animals, the researchers found. Instead, C/EBP teamed up with a group of different proteins, including several that are known to bind cell-growth genes. Additional experiments revealed that the protein conglomeration shuts off a gene called c-myc, which is crucial for initiating liver cell growth. Moreover, c-myc did not turn on when old animals had half their liver resected, but it did in similarly treated young animals. The researchers propose that C/EBP squelches duplication of old liver cells through a mechanism different from that for young cells--by muzzling genes rather than by binding to Cdks.
The team also found that concentrations of one gang member, the Brm protein, were higher in older animals than in younger ones. Adding Brm to cell contents from young livers made C/EBP abandon Cdks and join the protein assembly found in old cells. The researchers propose that extra Brm shifts C/EBP's associations.
"The formation of this C/EBP complex might explain how the liver loses its capacity to regenerate itself," says biochemist Steven McKnight of the University of Texas Southwestern Medical Center in Dallas. But molecular biologist Peter Johnson of the National Cancer Institute in Frederick, Maryland, cautions that no one knows whether the protein group is what's inhibiting growth in old liver cells. If the Brm bunch is responsible, the result could apply to other tissues as well: Alterations in Brm concentrations might also shift protein groupings in tissues such as the brain, where C/EBP is also produced, says cancer researcher Marie Classon of Harvard University. Future work should address whether lowering C/EBP or Brm quantities in old animals is enough to restore liver resilience or whether other barriers must also be lifted. Such work might reveal ways to give old livers the flexibility of youth.
--R. John Davenport; suggested by Greg Liszt
May 21, 2003
Science of Aging Knowledge Environment. ISSN 1539-6150