Sci. Aging Knowl. Environ., 18 December 2002
Vol. 2002, Issue 50, p. nw166
[DOI: 10.1126/sageke.2002.50.nw166]


Random Acts

Why senescence hits some cells earlier than others

R. John Davenport;2002/50/nw166

Key Words: WI-38 • BJ • polycomb • INK4a • RING finger

Like wind-up toy soldiers, cultured cells don't march forever. One by one, they grind to a halt, entering a stagnant state known as senescence. New work illuminates the interplay between proteins that control senescence and helps explain why apparently identical cells--and different cell types--don't senesce at the same time.

The relevance of senescence remains controversial, but it might mothball potentially cancerous cells (see "Dangerous Liaisons") or promote aging (see "More Than a Sum of Our Cells" and Campisi Perspective). Scientists hope to outline the pathways that cells take toward senescence, and they've made some progress. They've found, for example, that when chromosomes lose their protective caps--known as telomeres--or DNA incurs damage, proteins p53 and pRB jump into action, triggering senescence. Crippling p53 or pRB allows cells to bypass the alarms and keep dividing.

A protein called Bmi-1 quiets a region of DNA that encodes two proteins that kick-start pRB and p53, respectively. Itahana and colleagues wondered whether Bmi-1's ability to shut down this chromosomal section restrains senescence. The researchers found that Bmi-1 concentrations in human lung fibroblasts--connective tissue cells--dropped when the cells senesced in culture. Then the team engineered these fibroblasts to manufacture copious amounts of Bmi-1. Like cells with inactive p53 or pRB, these cells divided more times than controls did, apparently ignoring the usual senescence triggers.

To determine which senescence pathway Bmi-1 influences, the team blocked either p53 or pRB in cells containing extra Bmi-1. Cells with shackled pRB divided only a normal number of times, whereas those with hogtied p53 lived longer than controls did. Because Bmi-1 circumvents senescence only when pRB is active, the researchers concluded that Bmi-1 extends cell life by interrupting the pRB pathway. Additional studies suggest that Bmi-1 acts by blocking production of a protein called p16, which normally activates pRB. Cells with a mutant form of Bmi-1 that senesce unusually quickly amass extra p16.

Further work reveals that p16 might doom some cells to senescence before telomeres disintegrate. When telomeres are still robust, cultures of lung fibroblasts without augmented Bmi-1 contain some p16-producing cells. The authors propose that extra Bmi-1 suppresses p16 only in those cells in which chance activation of p16 has already occurred, allowing them to persist until their telomeres shorten. Supporting the hypothesis, another fibroblast cell line--derived from foreskin--that didn't make p16 did not divide longer than normal when given extra servings of Bmi-1.

Researchers had thought that Bmi-1 quenches the p53 and pRB pathways, but the new study suggests that Bmi-1 throttles only pRB, at least in some types of cells. The observations also clarify why cells of the same type and age don't all divide the same number of times and then stop, says oncologist Gordon Peters of the London Research Institute in the United Kingdom. The results suggest that spontaneous--and randomly occurring--changes in the p16 pathway that override p53 underlie the variation in lung fibroblast cells. The information will help researchers understand why cells wind down differently with age.

--R. John Davenport

K. Itahana, Y. Zou, Y. Itahana, J.-L. Martinez, C. Beausejour, J. J. L. Jacobs, M. van Lohuizen, V. Band, J. Campisi, G. P. Dimri, Control of the replicative life span of human fibroblasts by p16 and the polycomb protein Bmi-1-1. Mol. Cell. Biol. 23, 389-401 (2002). [Abstract] [Full Text]

December 18, 2002 Citation: R. J. Davenport, Random Acts. Science's SAGE KE (18 December 2002),;2002/50/nw166

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