Regulation of Death Ligand-Induced Killing

Project: Research project

Description

? DESCRIPTION (provided by applicant): Because apoptosis, a biochemically distinct form of cell death, is one of the major responses triggered in cancer cells by either chemotherapy or immunotherapy, there has been substantial interest in understanding regulation of the apoptotic process. Studies performed over the past two decades have demonstrated that death receptors, a subfamily of the tumor necrosis factora receptor superfamily, play critical roles in the response
to certain cancer chemotherapeutic agents, to death ligands such TNF?-related apoptosis-inducing ligand (TRAIL) and Fas ligand, and to cytotoxic lymphocytes that express these ligands. Thus, improved understanding of factors that determine whether death receptor ligation will induce cell death or not has potential implications for certain aspects of both cancer chemotherapy and immunotherapy. Our preliminary studies have provided new insight into multiple different aspects of death receptor regulation. Working backwards from measurement of cell surface death receptors, we have shown that the outcome of death ligand signaling is impacted by factors that affect trafficking of death receptors to the cell surface, stability of deth receptor mRNA, and transcriptional activation of death receptor genes. To build on these observations, we now propose to 1) elucidate the pathway by which protein kinase C inhibits trafficking of death receptors to the cell surface, 2) investigate how death receptor mRNA half-life is regulated by RNA binding proteins to produce cells that exhibit Bcl-2 independent vs. Bcl-2 inhibitable death ligand- induced signaling, and 3) determine the mechanism by which PARP inhibitors, acting through the transcription factor Sp1, enhance death ligand-induced apoptosis in AML cells and clinical AML samples ex vivo. If successful, the proposed experiments will not only provide new insight into the regulation of death receptor-mediated apoptosis, but also generate preclinical data in further support of testing a novel death ligand/chemotherapy combination.
StatusActive
Effective start/end date5/13/154/30/20

Funding

  • National Institutes of Health: $373,020.00
  • National Institutes of Health: $373,020.00

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Death Domain Receptors
Ligands
Apoptosis
Cell Death
Immunotherapy
Neoplasms
Sp1 Transcription Factor
Drug Therapy
Messenger RNA
Fas Ligand Protein
RNA-Binding Proteins
Cell Surface Receptors
Combination Drug Therapy
Protein Kinase C
Transcriptional Activation
Ligation
Half-Life
Necrosis
Lymphocytes

ASJC

  • Medicine(all)