Genetics

DUAL ROLE: Ronald DePinho, a professor at the Albert Einstein College of Medicine, helped to both identify INK4a as a tumor suppressor and to demonstrate its involvement in the Rb and p53 pathways. M. Serrano, H. Lee, L. Chin, C. Cordon-Cardo, D. Beach, R.A. DePinho, "Role of the INK4a locus in tumor suppression and cell mortality," Cell, 85:27-37, 1996. (Cited in more than 134 publications to date) Comments by Ronald A. DePinho, Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, N.Y. Tumor suppressors rarely work alone. This paper clarified the role of the INK4a gene and its protein products in tumor suppression and cell mortality or senescence. In the series of papers that followed, researchers confirmed INK4a's role in the pathogenesis of melanoma and demonstrated its intriguing interaction with the tumor suppressors p53 and Rb, genes frequently neutralized in a number of human cancers. Along with their teams, coauthors Ronald A. DePinho, a professor of microbiology and immunology and the Feinberg Senior Scholar in Cancer Research at the Albert Einstein College of Medicine, and David Beach, a staff scientist at Cold Spring Harbor Laboratory in Cold Spring Harbor, N.Y., each knocked out an exon, an expressed region of DNA, in the INK4a gene. The exon was known to be essential for the encoding of the protein p16 INK4a , shown in earlier studies to be a component of the Rb pathway. Although DePinho suggests that INK4a's status as a tumor suppressor was the "major report of this paper," he's quick to attribute the article's popularity to its revealing a great deal more, including INK4a's role in "enabling cells to enter and exit from . . . replicative senescence." Follow-up studies revealed some more unexpected implications. When they first started their research, DePinho and his colleagues didn't realize that INK4a also encoded the protein p19 Arf , a finding published in December 1995 by a team from St. Jude's Children's Research Hospital in Memphis, Tenn. (D.E. Quelle et al., Cell, 83:993-1000, 1995). The St. Jude's researchers had reported that the INK4a gene encoded the two unrelated proteins p16 INK4a and p19 Arf , and that these proteins were capable of inducing cell-cycle arrest. While investigating INK4a, DePinho's and Beach's teams had discovered that cells deficient for both p16 INK4a and p19 Arf led to the breeding of mice prone to the development of fibrosarcomas and B-cell lymphomas. In a later study, DePinho's group confirmed that INK4a deficiency is directly linked to melanoma susceptibility (L. Chin et al., Genes and Development, 11:2822-34, 1997). Then things got really interesting. Surprisingly, the same study also found that the tumor suppressor p53 was not mutated in those INK4a-deficient cancerous cells. "The lack of p53 mutations in cancer is very unusual because p53 is the most commonly mutated tumor suppressor in human cancers," explains DePinho. "Whenever you see an arrangement like that, you think that, perhaps, INK4a and p53 might be on the same pathway at some genetic level." Subsequent research by the St. Jude's team (T. Kamijo et al., Cell, 91: 649-60, 1997) demonstrated that there was in fact a functional link between the p19 Arf and p53 pathways in melanoma. So INK4a had been implicated in both the Rb pathway via p16 INK4a and the p53 pathway via p19 Arf . DePinho's team later showed that p19 Arf enables p53 to function normally by binding to and neutralizing an inhibitor of p53, the protein MDM2. "When you lose p19 Arf , . . . MDM2 then works unopposed and can really squash p53 activity," says DePinho of research just published (J. Pomerantz et al., Cell, 92:1-20, 1998). He and his colleagues are currently trying to understand how p19 Arf actually ties into the pathways that target p53 for degradation. They also would like to determine why one gene should encode two distinct gene products. "The fact that its two structurally and biochemically dissimilar products modulate different tumor suppressor pathways makes INK4a uniquely effective and, at the same time, exquisitely vulnerable as a tumor suppressor," maintains DePinho. In future studies at Harvard Medical School, where he'll be moving to this June, he hopes to discover why cells should be put at such a high risk for neoplasia in order to gain this high level of genomic organization.

Genetics

The Scientist Staff

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