Cancer

M. Serrano, A.W. Lin, M.E. McCurrach, D. Beach, S.W. Lowe, "Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a," Cell, 88:593-602, March 7, 1997. (Cited in more than 180 papers since publication)Comments by Scott W. Lowe, associate professor, Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y.Scott W. Lowe and postdoctoral fellow Maria SoengasAn unpublished 15-year-old observation of an obscure cell line, dusted off and revisited, helped Scott W. Lowe and colleagues better understand oncogene cooperation. During Lowe's grad student years in the mid-'80s, he worked with Massachusetts Institute of Technology's Earl Ruley (now a professor at Vanderbilt University). Ruley had previously inferred that the oncogene ras might cause cell cycle arrest in the "strange" cell line REF52.1 REF52 "was unlike most immortal cell lines in that ras would require two oncogenes to transform it, whereas in the classic 3T3 line, you just need one," Lowe explains. Introducing ras into that cell line indeed arrested the cell cycle. That observation remained unpublished because it occurred only in REF52 and because the adenovirus E1A oncogene had a greater effect. The scientists lacked retroviral gene transfer techniques that would allow them to expand their finding into primary cell cultures. They also couldn't explain how introducing a known tumor-causing gene could have an antiproliferative effect.After Lowe's group shelved its findings, p53 began its rise to prominence as a definitive tumor suppressor.2,3 Few other well-characterized tumor suppressors existed at the time, so Lowe decided to see how p53 interacted with ras. "We imagined that ras would induce p53 and E1A would block this induction," Lowe notes. "When we did the experiment, ras did induce p53, but E1A did it even more."When Lowe joined Cold Spring Harbor Laboratory in 1995, he decided to revisit exactly why and how. By then, scientists had developed better retroviral gene transfer techniques, which allowed Lowe to do what he couldn't do originally. When he put ras into primary cells, "sure enough, just like that immortal REF52 cell line, they stopped growing, too," Lowe recalls. "And that's when we got really excited." Lowe expanded his investigation to include p16 because that tumor suppressor gene's founders, Manuel Serrano and David Beach, also worked at Cold Spring Harbor. Knocking out p16 in mice, then adding ras embryonic fibroblasts transformed those primary mouse embryo fibroblasts into cancerous cells.4"Now you had the p53 tumor suppressor involved and then potentially the p16 tumor suppressor involved," Lowe recalls. "These are the two most frequently mutated changes in human cancer." They eventually showed that ras could induce both the p16 protein and the p53 protein, and in doing so, halt cell division. The group then stumbled onto senescence as the cycle-ceasing mechanism triggered by the interaction of ras and the two tumor suppressors. Serrano's wife, Maria Blasco, then a postdoc in Carol Greider's Cold Spring Harbor lab, wondered aloud if the cells that Lowe's group observed were actually senescent. Lowe and colleagues quickly confirmed that hunch.Lowe notes that ras's role in transformation underscores the complexity of the interaction between oncogenes and tumor suppressors and links them both to senescence. "Maybe one reason [p53 and p16] are there is to essentially counter the proliferative signal induced by ras." Lowe and colleagues have reevaluated and refined their theory of oncogene interaction. "We probably misinterpreted to some extent the involvement of p16 in this process." They have also mapped the functions downstream of ras involved in promoting arrest--signaling through a mitogen activating protein (MAP) kinase cascade.5Lowe predicts that more researchers will link other oncogenes to senescence, thus broadening senescence's role. He compares senescence to apoptosis; both are common programs triggered by diverse signals under a variety of conditions that functionally stop cell proliferation. "Perhaps senescence isn't a program that is only linked to replicative aging ... but has other roles as well, maybe in terms of protecting cells against stress." However, if both processes are truly broad and global (and if senescence can be proven to truly occur in vivo, rather than just in vitro), then Lowe poses another mystery: "Why will some cells apoptose and other cells senesce?"References1. B.R. Franza et al., "Invitro establishment is not a sufficient prerequisite for transformation by activated ras oncogenes," Cell, 44:409-18, 1986.2. C.A. Finlay et al., "The p53 proto-oncogene can act as a suppressor of transformation," Cell, 57:1083-93, 1989.3. P.W. Hinds et al., "Mutant p53 DNA clones from human colon carcinomas cooperate with ras in transforming primary rat cells--a comparison of the hot-spot mutant phenotypes," Cell Growth and Differentiation, 1:571-80, 1990.4. M. Serrano et al., "Role of the INK4a locus in tumor suppression and cell mortality," Cell, 85:27-37, 1996.5. A.W. Lin et al., "Premature senescence involving p53 and p16 is activated in response to constitutive MEK/MAPK mitogenic signaling," Genes and Development, 12:3008-19, 1998.

Cancer

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