Search

A central issue in the regulation of apoptosis by the Bcl-2 family is whether its BH3-only members initiate apoptosis by directly binding to the essential cell-death mediators Bax and Bak, or whether they can act indirectly, by engaging their pro-survival Bcl-2–like relatives. Contrary to the direct-activation model, we show that Bax and Bak can mediate apoptosis without discernable association with the putative BH3-only activators (Bim, Bid, and Puma), even in cells with no Bim or Bid and reduced Puma. Our results indicate that BH3-only proteins induce apoptosis at least primarily by engaging the multiple pro-survival relatives guarding Bax and Bak.

Apoptosis provoked by DNA damage requires the p53 tumor suppressor, but which of the many p53-regulated genes are required has remained unknown. Two genes induced by this transcription factor,noxaandpuma(bbc3), stand out, because they encode BH3-only proteins, proapoptotic members of the Bcl-2 family required to initiate apoptosis. In mice with eithernoxaorpumadisrupted, we observed decreased DNA damage–induced apoptosis in fibroblasts, although only loss of Puma protected lymphocytes from cell death. Puma deficiency also protected cells against diverse p53-independent cytotoxic insults, including cytokine deprivation and exposure to glucocorticoids, the kinase inhibitor staurosporine, or phorbol ester. Hence, Puma and Noxa are critical mediators of the apoptotic responses induced by p53 and other agents.

Numerous cancer-prone strains of mice have been created by the introduction of candidate tumor-promoting genes into fertilized eggs. Each transgenic strain is predisposed to develop specific types of tumors, but they usually arise stochastically because of the need for spontaneous mutation of genes that collaborate with the introduced oncogene. These mice are providing insights into the effects of individual oncogenes on cellular proliferation, differentiation, and viability, as well as on oncogene cooperativity. Their predisposed state imposes sensitivity to viral and chemical carcinogenesis, and the mice should prove valuable in tests of potential carcinogens, therapies, and preventive measures.

A critical issue for cancer biology and therapy is whether most tumor cells or only rare “cancer stem cells” sustain tumor growth. Although the latter model seems supported by the minute proportion of human leukemia cells that can grow in immunodeficient mice, evidence that more than 10% of cells in many mouse leukemias and lymphomas are transplantable challenges its generality.