Survival Factors and Apoptosis

For this article, Tom Hollon interviewed Anne Brunet, a postdoctoral fellow in the division of neurosciences, Children's Hospital, Harvard Medical School. Data from the Web of Science (ISI, Philadelphia) show that Hot Papers are cited 50 to 100 times more often than the average paper of the same type and age. A. Brunet, A. Bonni, M.J. Zigmond, M.Z. Lin, P. Juo, L.S. Hu, M.J. Anderson, K.C. Arden, J. Blenis, M.E. Greenberg, "Akt promotes cell survival by phosphorylating and inhibiting a forkhead transcription factor," Cell 96: 857-68, March 19, 1999. (Cited in 239 papers) Courtesy of Anne BrunetAnne BrunetCell life depends on stringent repression of apoptosis, or programmed cell death. Repressing transcription of cell death genes is one way of preventing apoptosis. Another method relies on the presence of extracellular stimuli called survival factors that transduce signal pathways that keep apoptosis in check. Many growth factors and hormones double as survival factors. This paper demonstrates a link between survival factors and transcriptional repression of genes that unleash cell death. Anne Brunet, a postdoctoral fellow in the division of neurosciences, Children's Hospital, Harvard Medical School, recalls that, in 1997, senior author Michael E. Greenberg, professor of neurology at Children's Hospital, published a paper in Science1 showing that a protein kinase called 'Akt' was crucial for transmitting signals from survival factors and mediating survival in neurons.2 Work by others quickly extended the discovery to other cell types. According to Brunet, the next step was to find out "how Akt exerted its survival effect and what were its substrates." One possibility was that Akt acted within the nucleus, repressing death genes by regulating transcription factors controlling death gene expression. But a plan of attack was not formulated until Brunet's team noticed a paper from Gary Ruvkun's laboratory, also at Harvard Medical School, published that same year.3 Ruvkin's group found that the pathway that activates Akt in Caenorhabditis elegans regulates a member of the Forkhead transcription factor family. Brunet's team decided to find out if a Forkhead transcription factor was controlled by neuronal survival signaling pathways involving Akt. They focused on FKHRL1, a Forkhead factor chosen for its high expression in the brain and similarity to the factor Ruvkun identified. In tissue culture experiments with neuronal and other cells, Brunet's group found that when growth factors are present, Akt phosphorylates FKHRL1. By a mechanism still not completely clear, phosphorylation causes FKHRL1 to be sequestered in the cytoplasm. When cells are starved of growth factors, FKHRL1 returns to its unphosphorylated state, enters the nucleus, and transcribes Fas ligand, a well-known cytokine that triggers cell death. "So survival signals allow cells to survive by preventing the activity of a death transcription factor," Brunet concludes. Brunet wonders if survival factor regulation of FKHRL1 has implications for neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's, all thought to be caused by the death of neurons. FKHRL1 could also be implicated in the excessive survival and proliferation of tumor cells.4 And there may be a diabetes connection: Insulin regulates FKHRL1. "More farfetched but still possible," she offers, "is the possibility that Forkhead transcription factors like FKHRL1 regulate lifespan." One function of Ruvkun's C. elegans factor is prolonging life. FKHRL1 may very well activate other apoptosis-related genes, so Greenberg's lab, where Brunet works, is tracking down FKHRL1-induced genes using microarray techniques, most recently with the aid of the new human genome sequence. Achieving a complete understanding of how these genes bring on self-destruction will be a milestone in apoptosis research. Brunet attributes the citations showered on the paper as the reward for a timely connection between survival signaling and gene regulation, and the influence their joining has had on diverse fields of research. Widespread occurrence of gene regulation through survival signaling underscores the value of further research, she says: "That the connection has been conserved throughout evolution, from worms to humans, emphasizes its general importance." Tom Hollon (thollon@starpower.net) is a freelance writer in Rockville, Md. References 1. H. Dudek et al., "Regulation of neuronal survival by the serine-threonine protein kinase Akt," Science, 275:661-5,1997. 2. S. Bunk, "Hot papers in signal transduction," The Scientist, 13[11]:15, May 24, 1999. 3. S. Ogg et al., "The Fork head transcription factor DAF-16 transduces insulin-like metabolic and longevity signals in C. elegans," Nature, 389:994-9,1997. 4. R.H. Medema et al., "AFX-like Forkhead transcription factors mediate cell-cycle regulation by Ras and PKB through p27kip1," Nature, 404:782-7, 2000.

Survival Factors and Apoptosis

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