Slugging it out: fine tuning the p53-PUMA death connection

Abstract

In response to DNA damage, the tumor suppressor p53 elicits a complex cellular response. In this issue of Cell, Wu et al. (2005) show that the transcription factor SLUG is induced by p53 and protects hematopoietic progenitor cells from apoptosis triggered by DNA damage. SLUG exerts this protective role by repressing Puma, a proapoptotic target of p53. PUMA is also a key coordinator of apoptosis mediated by both nuclear and cytoplasmic functions of p53 (Chi-puk et al., 2005).

Figure 1

Role of PUMA and SLUG in Modulating Apoptosis Mediated by p53 Once activated by DNA damage, p53 induces various target genes, including Puma (which encodes a proapoptotic BH3-only protein) and Slug (which encodes a transcription factor that represses Puma transcription). In most cells, the amount of SLUG may not be sufficient to repress Puma and prevent apoptosis. Importantly, in hematopoietic progenitor cells, the endogenous amount of SLUG protein is sufficient to repress Puma and limit apoptosis induced by DNA damage. Also shown is the role of PUMA and p53 in coordinating cell death in the cytoplasm. Here, PUMA binds Bcl-xL and displaces p53, thereby allowing p53 to directly activate Bax and induce permeabilization of mitochondria and cell death.