Philanthropy For Basic Science: Telomeres

Genetic Mechanisms Regulating Replicative Aging in Differentiated Human Cell Populations

DR. COHEN and his team made several striking findings, including a discovery about how the shortening of telomeres can activate replicative senescence. They found that telomere shortening in human fibroblasts causes up-regulation of the gene called Smurf2, and that such up-regulation is enough to produce the senescence phenotype. Smurf2 can induce senescence even in the absence of detectable DNA damage or stress response, the researchers found. Smurf2's senescence effect could be prevented by simultaneous expression of two viral oncoproteins, E6 and E7 (proteins of human papillomavirus 16), but not by either protein alone. "Smurf2 is the first gene found to be both upregulated by telomere attrition, and sufficient to induce senescence," Dr. Cohen reported. In a separate study, they compared human mammary epithelial cells (HMECs) grown in the usual way on plastic dishes and those cultured on fibroblast feeder dishes. Results varied with the culture medium. "We found that gene expression profiles of senescence in HMECs of the same lineage cultured under different conditions showed surprisingly little commonality. Moreover, neither profile resembles the replicative senescence signature of fibroblasts," Dr. Cohen wrote. Finally, the researchers reported finding what they called "the Shangri-La effect": Cells immortalized by the telomerase enzyme still undergo "aging" at the genetic level, they said.