Slug Antagonizes p53-Mediated Apoptosis of Hematopoietic Progenitors by Repressing Puma.

The discovery that Slug has a vital anti-apoptotic role in the normal response of hematopoietic progenitors to genotoxic stress compelled us to investigate the underlying cellular and molecular mechanism(s) of this effect. Here we show that, although the development of myeloid progenitors in Slug^−/− mice is not impaired under steady-state conditions, their ability to repopulate the compartment after γ-irradiation is reduced. We demonstrate that the radiation-induced death of Slug^−/− mice exclusively reflects bone marrow failure and show that Slug protects mice from γ-irradiation-induced death in a cell-autonomous manner. We also establish that Slug confers radioprotection by inhibiting the mitochondria-dependent apoptotic pathway activated by γ-irradiation in hematopoietic progenitors. We show that Slug acts as a transcriptional repressor by directly antagonizing p53-mediated upregulation of the BH3-only gene Puma, which was recently shown to encode a critical mediator of p53-induced apoptosis. Finally, we provide evidence for a novel feedback loop in the hematopoietic progenitor cells after DNA damage: Slug is itself induced by p53. Thus, the survival of hematopoietic progenitor cells after genotoxic stress relies on induction of Slug by p53 and Slug-mediated repression of Puma.