The mechanism by which cells that are subjected to agents that induce DNA damage and subsequently undergo either cell cycle arrest and repair or cell death has been elusive. In particular, the involvement of p53 in either pathway, whether in a cancer cell or normal tissue, has been under intense scrutiny, and the studies presented in this manuscript bring our understanding of its role a step forward. In hematopoietic cells, γ-irradiation results in upregulation of p53, and this event induces cell cycle arrest and subsequent DNA repair or can affect cellular events that lead to apoptotic cell death. Using a mouse model, the authors extend their initial work to demonstrate that loss of Slug, a member of the snail family of zinc-finger transcription factors, renders both mature and precursor hematopoietic cells more sensitive to radiation. They show that expression of the transcriptional repressor, Slug, is induced by p53 and protects hematopoietic precursors from p53-mediated apoptosis. PUMA, a cytoplasmic factor that enhances p53-dependent apoptosis, is also induced by p53. Here, they show that Slug down-modulates PUMA expression but not p53 activation. Their results place Slug downstream of p53 activation and demonstrate that it directly affects PUMA expression. Finally, mice that lack Slug but have PUMA expression are more sensitive to radiation; however, in mice where Slug and PUMA are both missing, survival is preserved and increased survival of hematopoietic precursors was noted.
Integrating the effects of p53 on cell survival and apoptotic cell death, and understanding how it modulates these choices in normal and malignant cells, is critically important. The work here sheds light on why late myeloid cells that express low levels of Slug are more sensitive to radiation-induced cell death, whereas early hematopoietic precursors where levels are high are less sensitive and are likely to follow a pathway of cell cycle arrest and repair rather than apoptosis. These findings, combined with work from others, are important not only in shedding light on the molecular details of p53-dependent apoptosis but also for highlighting areas where treatment may be targeted. Looking for agents that up-regulate Slug may help protect cells, and, in particular, hematopoietic cells, from chemotherapy and radiation damage and enable higher doses of therapy or combined modalities that are at the present time too toxic. The question will be what effect increasing Slug will have on the tumor cell. It is not yet known whether down-modulating PUMA alone will be sufficient to block apoptosis and whether other signaling cascades will be affected by Slug that not only modulate p53-associated events and apoptosis but also cellular repair. Nonetheless, the work has shed light on both the transcriptional and cytoplasmic effects of p53.
