Cell Cycle

Edited by: Eugene Russo C. Deng, P. Zhang, J.W. Harper, S.J. Elledge, P. Leder, "Mice lacking p21CIP1/WAF1 undergo normal development, but are defective in G1 checkpoint control," Cell, 82, 675-84, 1995. (Cited in more than 170 papers through June 1997) Comments by Philip Leder, Harvard Medical School The gene p21CIP1/WAF1 inhibits the proper functioning of cyclin-dependent kinases (CDKs), molecules that help to control cellular duplication. Although p21CIP1/WAF1 is known to be regulated by the tumor suppressor gene p53, the extent of its participation in p53 function is not fully understood: The gene has some role in the pathway that begins with the disruption of p53 and culminates in tumor growth. In this paper, according to Philip Leder, a professor of genetics at Harvard Medical School and a senior investigator of the Howard Hughes Medical Institute, p21CIP1/WAF1-deficient mice were created by using targeted gene disruption in order to pinpoint the p53 functions for which p21CIP1/WAF1 is responsible. DEFINING ROLES: Philip Leder's team found that p21CIP1/WAF1 was involved in some of p53 functions. Leder points out that "p53 is involved in two, among many other, fundamental processes. It is somewhere within a pathway that leads to cell-cycle checkpoints in response to DNA damage. It also can lead . . . to apoptosis. We were interested in transformation and how genes collaborate to produce these effects." By monitoring the order and timing of cell cycle events at controls known as checkpoints, cells are able to maintain genomic stability and prevent mutations that disrupt normal development. "If you interfere with a checkpoint, presumably you allow the accumulation of mutations in DNA, which might lead to transformation," he explains. "Alternatively, if you interfere with the apoptotic response, you get continuous proliferation of cells that should have died. This genetic experiment would allow us to say whether p53 is involved in one or both of these pathways." Leder's team discovered that p21CIP1/WAF1 participates in only some of the known p53 functions. "We found that the loss of p21CIP1/WAF1 definitely did involve or result in the loss of the G1 checkpoint control-a major loss, but not a complete loss-with no effect that we could discern on apoptosis." In its ongoing observation of the mice, the team has obtained some curious results. The p53-deficient mice display a rapid rate of early tumorigenesis. Because p21CIP1/WAF1 is regulated by p53, one might expect that p21CIP1/WAF1 -deficient mice would also exhibit increased rates of tumorigenesis. This is not the case. "There is a very high instance of lymphoma and other tumor sarcomas occurring in p53-deficient mice," notes Leder. "In p21CIP1/WAF1 -deficient animals, we don't see this increased risk for lymphoma genesis or actually the occurrence of any other tumor. Maybe we haven't waited long enough yet, but that's our result to date. And it leads us to think that the apoptotic response is as important an element [as the role of p21CIP1/WAF1 ] in tumorigenesis due to p53." The paper's high number of citations can be attributed to two factors, Leder maintains. "Number one, there's enormous interest in cell-cycle control, and the role of modifiers like p21CIP1/WAF1 is a very important one. Number two, this interest has generated a lot of requests for the animal model itself and for the cells that are derived from it. I guess these people [who are citing the article] are using these materials and hopefully learning very important things from them." Leder hopes to continue research on p21CIP1/WAF1 and its potential role in the development of cancer. "Loss of p21CIP1/WAF1 by itself may not be sufficient to increase cancer risk," he reports, "but we might elucidate cancer risk in conjunction with the action of other oncogenes. So we're looking at the genetic interaction of p21CIP1/WAF1 loss with some dominant oncogenes, which we have [obtained] in the laboratory by appropriate mating experiments." Leder would also like to use radiation tumorigenesis in p21CIP1/WAF1-deficient animals to test the function of p21CIP1/WAF1. He notes: "By using radiation to stress the DNA repair mechanism, [and in so doing] stress the cell-cycle control mechanism in which p21CIP1/WAF1 is clearly involved, we should be able to investigate whether radiation-induced tumorigenesis is accelerated in the absence of this gene."

Cell Cycle

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