Slug, a highly conserved zinc finger transcriptional repressor, protects hematopoietic progenitor cells from radiation-induced apoptosis in vivo

Abstract

We show here that a zinc finger transcriptional repressor, Slug, which is aberrantly upregulated by the E2A-HLF oncoprotein in pro-B cell acute leukemia, functions as an antiapoptotic factor in normal hematopoietic progenitor cells. Slug(-/-) mice were much more radiosensitive than wild-type mice, dying earlier and showing accentuated decreases in peripheral blood cell counts, as well as abundant microhemorrhages and widely disseminated bacterial microabscesses throughout the body. Slug expression was detected in diverse subsets of hematopoietic progenitors, but not in more differentiated B and T lymphoid cells, and there was a significant increase in apoptotic (TUNEL-positive) bone marrow progenitor cells in irradiated Slug(-/-) mice compared to wild-type controls. These results implicate Slug in a novel survival pathway that protects hematopoietic progenitors from apoptosis after DNA damage.

Snai1 and Snai2 collaborate on tumor growth and metastasis properties of mouse skin carcinoma cell lines

“…These results are also in line with the recent observation that SNAI1 expression is a requisite for lymph node metastasis of human breast carcinoma cells (Olmeda et al, 2007b). On the other hand, the strong influence of Snai2 silencing in reduction of liver and lung metastasis could be related to the cell survival properties (Inoue et al, 2002;Perez-Losada et al, 2003;Kajita et al, 2004) or the specific migration properties conferred by Snai2 (Barrallo-Gimeno and Nieto, 2005;Elloul et al, 2005;Come et al, 2006) that could restrain effective lung and liver colonization in its absence.…”

Critical role for transcriptional repressor Snail2 in transformation by oncogenic RAS in colorectal carcinoma cells

“…In addition to causing loss of viability in RAS mutant mesenchymal cells, Snail2 knockdown increases the sensitivity of these cells to cytotoxic drugs. Snail2 inhibition has previously been shown to sensitize cells to DNA-damaging agents, in part by directing the p53 response away from apoptosis (Inoue et al, 2002;Perez-Losada et al, 2003;Kajita et al, 2004;Wu et al, 2005;Vannini et al, 2007;Vitali et al, 2008;Kurrey et al, 2009). Although the function of Snail2 as a transcriptional regulator does not make it an attractive target for pharmacological targeting, the data presented here suggest that its inhibition could be a good way of targeting some of the most intractable tumour types, those with a mutant RAS oncogene and a mesenchymal phenotype.…”

“…Although the function of Snail2 as a transcriptional regulator does not make it an attractive target for pharmacological targeting, the data presented here suggest that its inhibition could be a good way of targeting some of the most intractable tumour types, those with a mutant RAS oncogene and a mesenchymal phenotype. The relatively mild phenotype of Snail2 knockout mice (Jiang et al, 1998;Inoue et al, 2002) suggests that ontarget inhibition of this factor may also be relatively free from unwanted side effects.…”

The dark side of a tumor suppressor: anti-apoptotic p53

“…An important clue was provided with the discovery that Slug, a member of the highly conserved Slug/Snail family of transcription factors, protected hematopoietic progenitor cells from radiation-and druginduced apoptosis. 104 As Slug expression appears to be confined to multiple subsets of hematopoietic progenitors and absent in more differentiated myeloid cells or pro-B and T-cells, these findings provided an elegant explanation why the former, but not the latter cell populations are protected from genotoxic stress. 105 Intriguingly, Slug was recently shown to be a direct transcriptional target of p53 antagonizing its pro-apoptotic activities.…”