Slug is a member of the Slug/Snail superfamily of evolutionarily conserved zinc finger transcriptional repressors. Slug was identified as a functional target of the E2A-HLF fusion oncoprotein in pro-B-cell acute leukemias, in which the E2A-HLF fusion gene was generated by the t(17:19)(q22;p13) chromosomal translocation. Slug is an orthologue of CES-1, which lies downstream of the CES-2 cell-death specification protein of Caenorhabditis elegans, leading our laboratory to a model of leukemogenesis in which E2A-HLF blocks an early step within an evolutionarily conserved cell death pathway. Thus, our laboratory has generated Slug -/- mice and showed that they were more radiosensitive than wild-type mice, dying earlier and at an increased rate after total-body-gamma-irradiation. The irradiated Slug -/- mice have increased apoptosis in hematopoietic stem cells and progenitors compared to irradiated wild-type control mice. My preliminary results further showed that Slug is expressed in subsets of hematopoietic stem and progenitor cells and that its expression is induced 10-fold in a p53-dependent manner in normal bone marrow cells within 2 hours after irradiation. Taken together, these findings indicate that Slug plays an important antiapoptotic role in hematopoietic progenitor cells that have been exposed to gamma-radiation-induced genotoxic stress. The discovery that Slug plays an antiapoptotic role in hematopoietic progenitors raises two key mechanistic questions that will be addressed in two individual specific aims: i) What are the signal transduction pathways downstream of gamma-irradiation-induced DNA damage that upregulate Slug expression? ii) What are the direct downstream targets of Slug in hematopoietic progenitors and what are the signal transduction pathways through which Slug attenuates the apoptotic machinery? The working hypothesis is that Slug negatively regulates p53-mediated apoptotic signaling pathways at a point downstream of p53 activation, leading to attenuation of gamma-radiation-induced apoptosis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32CA103726-02
Application #
6772425
Study Section
Special Emphasis Panel (ZRG1-F05 (20))
Program Officer
Lohrey, Nancy
Project Start
2003-07-01
Project End
2006-06-30
Budget Start
2004-07-01
Budget End
2005-06-30
Support Year
2
Fiscal Year
2004
Total Cost
$47,296
Indirect Cost
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
076580745
City
Boston
State
MA
Country
United States
Zip Code
02215
Wu, Wen-Shu; Heinrichs, Stefan; Xu, Dong et al. (2005) Slug antagonizes p53-mediated apoptosis of hematopoietic progenitors by repressing puma. Cell 123:641-53