Targeted Disruption of the Low-Affinity Leukemia Inhibitory Factor-Receptor Gene Causes Placental, Skeletal, Neural and Metabolic Defects and Results in Perinatal Death

The low-affinity receptor for leukemia inhibitory factor (LIFR)* interacts with gp130 to induce an intracellular signal cascade, The LIFR-gp130 heterodimer is implicated in the function of diverse systems, Normal placentation is disrupted in LIFR mutant animals, which leads to poor intrauterine nutrition but allows fetuses to continue to term. Fetal bone volume is reduced greater than three-fold and the number of osteoclasts is increased six-fold, resulting in severe osteopenia of perinatal bone. Astrocyte numbers are reduced in the spinal cord and brain stem. Late gestation fetal livers contain relatively high stores of glycogen, indicating a metabolic disorder. Hematologic and primordial germ cell compartments appear normal. Pleiotropic defects in the mutant animals preclude survival beyond the day of birth

Protein-based therapeutic approaches targeting death receptors

Death receptors (DRs) are a growing family of transmembrane proteins that can detect the presence of specific extracellular death signals and rapidly trigger cellular destruction by apoptosis. Eight human DRs (Fas, TNF-R1, TRAMP, TRAIL-R1, TRAIL-R2, DR-6, EDA-R and NGF-R) have been identified. The best studied to date is Fas (CD95). Expression and signaling by Fas and its ligand (FasL, CD95L) is a tightly regulated process essential for key physiological functions in a variety of organs, including the maintenance of immune homeostasis. Recently, strong evidence has shown that dysregulation of Fas expression and/or signaling contributes to the pathogenesis of tissue destructive diseases such as graft-versus-host disease, toxic epidermal necrolysis, multiple sclerosis and stroke. With these new developments, strategies for modulating the function of Fas signaling have emerged and provided novel protein-based therapeutic possibilities that will be discussed herein. Selective triggering of DR-mediated apoptosis in cancer cells is an emerging approach that is being intensely investigated as a mode of cancer therapy. Local administration of Fas agonists, and more promisingly, systemic use of soluble recombinant forms of TRAIL have shown efficacy in preclinical models of the disease. Developments in this field that may have important clinical implications for the treatment of cancer are reviewed