The survival of multicellular organisms depends on the ability to evade potentially lethal DNA damage while minimizing the number of heritable mutations. To achieve this protection, mammalian blood cells have evolved elaborate surveillance mechanisms that monitor the structure of chromosomes and coordinate cell cycle progression, DNA repair and apoptosis. Recent data from the applicant's laboratory indicate that Slug, an antiapoptotic transcription factor that is aberrantly upregulated in leukemias that express the E2A-HLF oncoprotein, functions in vivo to protect hematopoietic progenitor cells from apoptosis induced by gamma-radiation. Biochemical studies demonstrate that Slug expression is upregulated in a p53-dependent manner after gamma- radiation, and suggest that Slug interferes with a p53-mediated apoptotic-signaling pathway in early hematopoietic progenitors at a point downstream of p53 activation. The resultant attenuation of programmed cell death after gamma-radiation allows these essential blood elements to recover and resume the task of reconstituting the hematopoietic compartment. This novel concept will be tested in three specific aims: (1) to establish that Slug acts cell autonomously as a pivotal regulator of apoptosis in myeloid/erythroid-restricted hematopoietic progenitor cells exposed to radiation and other genotoxic agents; (2) to test the hypothesis that Slug also plays a crucial role in the survival of normal hematopoietic stem cells (HSCs) after radiation-induced DNA damage; and (3) to elucidate the genetic programs upstream and downstream of the Slug zinc-finger transcriptional repressor that promote normal hematopoietic progenitor cell survival after genotoxic doses of radiation. These studies will benefit from close collaboration with Dr. Koichi Akashi, an expert in the fluorescence-activated sorting of HSCs and other early blood progenitors, and with Dr. Barbara Conradt, a former member of the Horvitz lab in Cambridge, who is moving forward on the genetic analysis of a similar cell survival pathway in the nematode, C. elegans. Successful completion of this 5-year project will promote understanding of how normal HSCs and other early progenitor cells survive genotoxic stress due to radiation and anticancer drugs, and will define the mechanism(s) by which Slug shifts the p53-dependent DNA damage response from apoptosis to cell survival. Most important, the information gained may suggest strategies that could be used to manipulate the Slug activated survival response in normal hematopoietic progenitors, in ways that might avoid or ameliorate the otherwise dose-limiting side effects of cancer therapy.
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