PROJECT 10: SLUG AS A KEY REGULATOR OF HEMATOPOIETIC STEM CELL SURVIVAL

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Slug is a transcriptional repressor that is expressed in pluripotent hematopoietic stem cells (HSCs). By studying mice deficient for both Slug and p53 or Slug and Puma, we have established that Slug acts downstream of p53 and upstream of Puma to control the fate of myeloid progenitor cells exposed to genotoxic stress in vivo. These findings implicate a vital anti-apoptotic role for Slug in the response of hematopoietic progenitors to genotoxic stress. However, these findings do not yet provide direct insight into the role of Slug in the protection of pluripotent hematopoietic stem cells (HSCs) from death due to DNA damage. Although we know endogenous Slug is normally expressed in both long- and short-term repopulating hematopoietic stem cells (HSCs), its roles in regulation of HSCs remain to be established. Thus, we will address these critical questions: (i) Is Slug indispensable for maintaining the integrity of HSC under steady-state conditions and, if so, by which mechanism(s)? (ii) Does Slug play an essential role in regulating HSCs self-renewal under genotoxic stress conditions?