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Tumor Suppression

For this article, Steve Bunk interviewed Ronald A. DePinho, professor of genetics, Dana Farber Cancer Institute, 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. J. Pomerantz, N. Schreiber-Agus, N.J. Liégeois, A. Silverman, L. Alland, L. Chin, J. Potes, K. Chen, I. Orlow, H-W. Lee, C. Cordon-Cardo, R.A. DePinho, "The INK4a tumor suppressor gene product, p19ARF,

By | September 4, 2000

For this article, Steve Bunk interviewed Ronald A. DePinho, professor of genetics, Dana Farber Cancer Institute, 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.

J. Pomerantz, N. Schreiber-Agus, N.J. Liégeois, A. Silverman, L. Alland, L. Chin, J. Potes, K. Chen, I. Orlow, H-W. Lee, C. Cordon-Cardo, R.A. DePinho, "The INK4a tumor suppressor gene product, p19ARF, interacts with MDM2 and neutralizes MDM2's inhibition of p53," Cell, 92:713-23, March 20, 1998. (Cited in more than 265 papers since publication)

All tumor suppressor pathways may not lead to their Rome, but for two pathways, a critical crossroads has been found on chromosome 9. This locus is called INK4a/ARF (inhibitor of cyclin-dependent kinase 4a/alternative reading frame). It encodes two proteins. One of them, p16INK4a, functions in the Rb (retinoblastoma) pathway. The other, p19ARF, is associated with the p53 pathway. A single mutation at this locus can disable both growth-control pathways, spelling disaster for protection against cancers.

"This gene is at the nexus of the two most important suppression pathways governing neoplasia," declares senior author Ronald A. DePinho, a professor of genetics at Dana Farber Cancer Institute, Harvard Medical School. He adds that the two gene products are encoded within overlapping reading frames, sharing exons or coding sequences.

Knowledge of the locus was derived from a genetic observation further enlightened by key biochemical data, which led to this paper demonstrating a link between the genetics and the biochemistry. The genetic observation, made in 1997 by both DePinho's lab (he was then at Albert Einstein College of Medicine) and by the team of Charles J. Sherr at St. Jude Children's Research Hospital in Memphis, Tenn., was that in the absence of the INK4a/ARF gene, tumors would arise but p53 would remain intact.1 The biochemical data, accumulated in 1997 by researchers at the Weizmann Institute of Science in Rehovot, Israel, and at the Frederick Cancer Research and Development Center in Frederick, Md., showed that a protein called MDM2 targets p53 for rapid degradation.2 Awareness arose of a negative feedback loop in which p53 activates transcription of MDM2, which then binds to p53, ensuring its eventual degradation.


Ronald A. Depinho
Then came this 1998 paper showing that one of the two proteins coded at the locus, p19ARF, prevents MDM2's degradation of p53. DePinho thinks that the paper's significance is enhanced because it provides genetic evidence that "ARF is a sensor of inappropriate proliferation brought about by loss of Rb, a concept solidified by observations from the Sherr and Lowe [Scott W. Lowe of Cold Spring Harbor Laboratory in New York] labs on apoptotic-oncogenic signaling." In other words, p19ARF's ability to block MDM2-induced degradation of p53 appears to enhance such p53 capabilities as growth inhibition and apoptosis. When ARF is mutated, it cannot act as a sensor of inappropriate cell cycle entry by premalignant cells, thereby leaving p53 unaware of the need to initiate cell death.

Following this paper, DePinho and colleagues did an experiment with mice, which normally have long telomeres and therefore do not experience the cell crisis associated with tumorigenesis. The researchers found that if they knocked out the telomerase RNA and the INK4a/ARF genes, the mice would go into crisis, just as human cells do, although these mice are less cancer prone than humans.3 In contrast, when telomerase knockout mice are mutant for p53, their chromosomes are allowed to fuse, break, and translocate in complex ways, generating a cytogenetic profile reminiscent of human tumors. Importantly, these mice now develop epithelial tumors (as in breast and colon cancers), a tumor spectrum similar to that seen in aged humans.4

Steve Bunk (sbunk@uswest.net) is a contributing editor for The Scientist.

References

1. E. Russo, ed., "Hot Papers: Genetics," The Scientist, 12 [9]:11, April 27, 1998.

2. E. Russo, ed., "Hot Papers: Cancer Research," The Scientist, 13 [12]:11, June 7, 1999.

3. R.A. Greenberg et al., "Short dysfunctional telomeres impair tumorigenesis in the INK4a(delta2/3) cancer-prone mouse," Cell, 97:515-25, May 14, 1999.

4. S.E. Artandi et al., "Telomere dysfunction promotes non-reciprocal translocations and epithelial cancers in mice," Nature, 406:641-5, Aug. 10, 2000.

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