Concepedia

p53- and Drug-Induced Apoptotic Responses Mediated by BH3-Only Proteins Puma and Noxa

Andreas Villunger, Ewa M. Michalak, Leigh Coultas, Franziska B. Mullauer, Günther Böck, Michael J. Ausserlechner, Jerry M. Adams, Andreas Strasser

Science · 2003 · 1.3K citations · 19 references

DOI

TL;DR

Apoptosis triggered by DNA damage depends on p53, but the specific p53‑regulated genes mediating this response were unclear until the BH3‑only proteins Puma and Noxa were identified as key pro‑apoptotic effectors. Loss of Puma or Noxa in mice reduces DNA‑damage–induced apoptosis in fibroblasts, and Puma deficiency also protects lymphocytes and various other cell types from p53‑independent cytotoxic stresses, demonstrating that Puma and Noxa are essential mediators of p53‑driven and other apoptotic pathways.

Abstract

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, noxa and puma ( bbc3 ), stand out, because they encode BH3-only proteins, proapoptotic members of the Bcl-2 family required to initiate apoptosis. In mice with either noxa or puma disrupted, 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.