E2F and Cell Proliferation: A World Turned Upside Down

Finally, there is the issue of nomenclature. E2F-1 is clearly an oncogene; when co-expressed with other known oncogenes, it leads to cellular transformation, thereby conforming to a widely accepted operational definition of an oncogene (3xJohnson, D.G, Ohtani, K, and Nevins, J.R. Proc. Natl. Acad. Sci. USA. 1994; 91: 12823–12827Crossref | PubMed | Scopus (224)See all References, 6xSingh, P, Wong, S.H, and Hong, W. EMBO J. 1994; 13: 3329–3338PubMedSee all References, 9xXu, G, Livingston, D.M, and Krek, W. Proc. Natl. Acad. Sci. USA. 1995; 92: 1357–1361Crossref | PubMed | Scopus (179)See all References). But the papers in this issue of Cell show that E2F-1 gene deletion also leads to cancer. In this sense, E2F-1 is also a tumor suppressor gene, indeed the first gene to claim membership in the two gene classes. Is this a nomenclatural sleight of hand, or does E2F-1 (and perhaps its sibs in the E2F family) really have a foot in both warring camps?The term “tumor suppressor gene” is often abused. The literature contains a number of reports in which the growth-inhibitory effects of certain genes are described following the ectopic expression of these genes in one or another type of cancer cell. A frequent conclusion is that the genes under study are functioning as tumor suppressors. In truth, an observation of a gene's growth-inhibitory powers says rather little about its normal physiologic role. After all, almost any gene will create some functional imbalance in a cell and slow down growth when it is ectopically expressed at high enough levels. Some oncogenes will even shut down cell growth.The present papers embrace a more useful and credible operational definition of a tumor suppressor gene: a gene which, when deleted from the genome of a cell or organism, encourages the appearance of a tumor. The two papers in this issue of Cell would seem to have satisfied these criteria by studying the effects of germline E2F-1 gene alteration on tumor susceptibility and by analyzing the growth properties of E2F−/− thymocytes in culture.Many of the tumor suppressor genes studied to date can cause cancer predisposition when present in the germline as mutant alleles in a heterozygous configuration. To be sure, the great bulk of the hyperplastic and neoplastic outcomes reported in these papers are associated with germline homozygosity of null alleles at the E2F-1 locus. But significantly, several of the mice that were heterozygous for an inactive allele of E2F-1 developed tumors similar to those seen in the homozygotes. By this criterion, germline null alleles of E2F-1 parallel the behavior of other known tumor suppressor genes.The slightly reduced ability of E2F-1−/− thymocytes to enter apoptosis in vitro would also seem to support the candidacy of E2F-1 as a tumor suppressor that operates on a cell autonomous basis. Here, however, there are alternative explanations: perhaps these E2F−/− thymocytes have not been allowed by their in vivo environment to differentiate in precisely the same way as their normal counterparts and therefore may not have developed to a state where they have acquired equal susceptibility to apoptosis. Still, these papers direct our minds to a new way of conceptualizing cellular growth control. Controllers may not be simply promoters or inhibitors of proliferation. Instead, as the authors of these reports would suggest, a single protein may act as either depending on its concentration in the cell.