Slug Antagonizes p53-Mediated Apoptosis of Hematopoietic Progenitors by Repressing puma

Abstract

In response to DNA damage, the p53 tumor suppressor can elicit either apoptosis or cell-cycle arrest and repair, but how this critical decision is made in specific cell types remains largely undefined. We investigated the mechanism by which the transcriptional repressor Slug specifically rescues hematopoietic progenitor cells from lethal doses of gamma radiation. We show that Slug is transcriptionally induced by p53 upon irradiation and then protects the damaged cell from apoptosis by directly repressing p53-mediated transcription of puma, a key BH3-only antagonist of the antiapoptotic Bcl-2 proteins. We established the physiologic significance of Slug-mediated repression of puma by demonstrating that mice deficient in both genes survive doses of total-body irradiation that lethally deplete hematopoietic progenitor populations in mice lacking only slug. Thus, Slug functions downstream of p53 in developing blood cells as a critical switch that prevents their apoptosis by antagonizing the trans-activation of puma by p53.

Transcriptomal profiling of the cellular response to DNA damage mediated by Slug (Snai2)

“…These observations indicated that p53 does not require Snai2 to activate the cell cycle checkpoint by arresting in G1. Moreover, these results indicate Snai2 does not require p53 for its DNA damage protective function in MEFs in agreement with previous data in haematopoietic precursors Perez-Mancera et al, 2005;Wu et al, 2005). To confirm that our approach could be used to study the role of the p53-responsive Snai2 DNA damage-associated target genesgene Snai2 in DNA damage response, we next examined whether known target genes were modulated in control and Snai2-deficient MEFs after DNA doxorubicin treatment.…”

“…Thus, constitutive activation of Snai2 could confer resistance properties to the tumour-target cells connecting DNA damage with the requirement of a critical level of Snai2 for cancer development. In agreement with these results, recently it has been shown Snai2 is a p53 target that antagonises p53-mediated apoptosis of haematopoietic progenitors (Wu et al, 2005). However, the effect of Snai2 on p53 target genes remains an open question (Haupt et al, 2006).…”

“…Analysis of the expression of the same set of genes revealed that overall expression was not altered in Snai2-deficient cells in response to doxorubicin treatment ( Figure 3B). The expression of the previously implicated Snai2-target gene Puma/bbc3 (Wu et al, 2005;Bermejo-Rodriguez et al, 2006) was not significantly modulated in Snai2-deficient cells in response to DNA damage. To confirm this result, we next measured the Puma/bbc3 protein levels in wild-type MEFs and Snai2-deficient MEFs after DNA damage induced by doxorubicin.…”

“…These results suggested that Snai2 expression was protecting cells from death by genetic alterations as a consequence of an inherent, basal level of genetic instability (Sanchez-Garcia, 1997;Pérez-Caro et al, 2005;Perez-Mancera et al, 2005). Consistent with this interpretation, in the haematopoietic system Snai2-deficient cells are radiosensitive to DNA damage (Inoue et al, 2002;Perez-Losada et al, 2003;Wu et al, 2005). In fact, SNAI2 expression seems to be associated with a patient's resistance to chemotherapeutic agents in human mesotheliomas (Catalano et al, 2004).…”

“…It has been previously shown that Snai2-deficient bone marrow cells are radiosensitive to DNA damage induced by g-irradiation (Inoue et al, 2002;Perez-Losada et al, 2003;Wu et al, 2005). p53 is centrally involved in the cellular response to DNA damage (Attardi et al, 2000).…”