Everything in Moderation... Even Tumor Suppressors

The Faculty of 1000, published by BioMed Central, is a Web-based literature awareness tool. F1000 provides a continuously updated guide to peer-reviewed papers, based on the recommendations of more than 1,400 leading scientists. In each issue, The Scientist publishes a review of some related papers highlighted by the Faculty of 1000, plus comments on new and notable research. For more information, visit www.facultyof1000.com. Homeostasis is an arguably underappreciated and powerful process that may yet receive its due, as scientists continue to knock out, mutate, and overexpress genes to clarify protein function. It is clear that these techniques contribute greatly to the understanding of life at the cellular, tissue, organ, and organismal level. However, models created with less potent functional dysregulation may mimic more accurately real-world physiology. Two groups of researchers have isolated functional truncated mutant forms of p53 with a wild-type allele in two different model systems, worm and mouse. Their observations bear similarities and differences that both hone and expand the role of this pivotal protein in homeostatic mechanisms. Nikki Holbrook, professor, Internal Medicine and Geriatrics at Yale University Medical School, points out in her F1000 commentary, "These findings are likely to prompt a large number of new investigations on the role of p53 in aging and its link to other putative mechanisms in the aging process, including stress responsiveness/resistance." The Mouse Because of its mutated presence in about 50% of human tumors, p53 is considered a major tumor suppressor in its wild-type form. While in vitro research has implicated additional roles for p53 in stress responses and aging, an in vivo model remained elusive. Larry Donehower, professor in the departments of molecular virology and microbiology and molecular and cellular biology at Baylor College of Medicine, Houston, and his doctoral candidate Stuart Tyner, now provide in vivo confirmation.1 Following an unexpected stem cell recombination event, Donehower generated mice with one wild-type p53 allele and a defective p53 allele. The mutant allele expresses a truncated RNA encoding a carboxy-terminal p53 fragment. The surprising results produced a give-and-take situation: there was increased activity of p53 and therefore enhanced resistance to tumor formation, but the mice aged earlier, with a greater than 20% decrease in lifespan. "The price of the cancer resistance is reduced longevity and appearance of an early aging phenotype," says Donehower. The two report human, age-related changes in the mutant mice including bone loss, hunched spine, dermal thinning, atrophy of muscle, liver, spleen, kidney and lymphoid tissue, slowed wound healing, and reduced white blood cell replacement. In the future, they plan to look at p53's role in normal stem cell function. Says Donehower, "If your stem cells aren't operating properly, it may affect organ homeostasis.... Whether the worm protein has the exact same biological function as mammalian p53 is questionable because worms don't develop tumors." The Worm Some proteins do not exist in some organisms, and until last year, that was presumed about p53 in the well-elucidated Caenorhabditis elegans system. Using additional algorithms, however, W. Brent Derry, a postdoctoral fellow in the laboratory of Joel Rothman at University of California, Santa Barbara, identified a "cryptic p53-like gene" they called cep-1. This C. elegans p53-like protein has a role in apoptosis, meiosis, and stress responses.2 Cep-1 encodes for a protein that contains not only the highly conserved DNA- binding domains but also an NH2-terminal transactivation domain similar to the human form of p53. Using a mutant form of cep-1 and RNAi, Derry demonstrated that cep-1 is required for DNA damage-induced cell death in the germ line but not the soma, and for normal chromosomal segregation during meiosis. Derry says that functional cep-1 is also needed for the worm's stress re-sponse to starvation, which allows the organism to enter the dauer state, a kind of suspended animation, until it finds food. Derry did notice some decrease in longevity in stressed mutant worms, but he was reluctant to liken this observation to the early-onset aging phenotype described by Donehower. "The main goal of cep-1 is to engage the apoptotic pathway in response to DNA damage in the germ line," Derry says. Germ cells may be the one location where higher levels of p53 are tolerated. "[Germ cells] are the keepers of the DNA for the next generation," says Mark Van Doren, assistant professor of biology at Johns Hopkins University. "In the germ line, the genome has to remain perfect; or, if it's not ... you have to have some way of getting rid of that genome, and p53 may have an enhanced role in the germ line specifically." In the soma, homeostasis is maintained through a tightly regulated balance of cell proliferation and cell death in which p53 is a major player. Tipping the balance either way results in pathogenesis. F1000 member Van Doren notes, "p53 seems to be expressed at high levels in the germ lines of a number of organisms where it's been studied." Perhaps, it is better to have fewer perfect progeny than more mutant progenitors. Susan Jenkins can be contacted at sjenkins@the-scientist.com. References 1. S. Tyner et al., "p53 mutant mice that display early ageing-associated phenotypes," Nature, 415:45-53, Jan. 3, 2002. 2. W. Brent Derry et al., "Caenorhabditis elegans p53: role in apoptosis, meiosis, and stress resistance," Science, 294:591-5, Oct. 19, 2001.

Everything in Moderation... Even Tumor Suppressors

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