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Screening and characterization of cyclic pentapeptide CXCR4 antagonists/inverse agonists using a pheromone responsive reporter gene in Saccharomyces cerevisiae: Utility of G protein coupled receptor constitutively active mutants

  • Zi-xuan Wang
  • Hirokazu Tamamura
  • Nicole Frilot
  • James Broach
  • Nobutaka Fujii
  • Stephen C. Peiper
Part of the Progress in Inflammation Research book series (PIR)

Abstract

CXCR4 is a chemokine receptor that belongs to the GPCR superfamily. It specifically transduces the signal of one CXC chemokine ligand, stromal cell derived factor 1 [1, 2], which has been designated CXCL12 in the current nomenclature assigned to members of the chemoattractant cytokine gene family [3]. This GPCR-ligand pair plays a critical role in programming the directed migration of multiple cell types during embryologic development, including neural, endothelial, and hematopoietic progenitors, as well as primordial germ cells [4]. Mice rendered nullizygous for either CXCR4 or CXCL12 by gene targeting die in utero with incomplete formation of the cerebellum, vascular system and the medullary hematopoietic compartment [5]–[7]. During adult life, CXCL12 is a chemoattractant for multiple subsets of leukocyte and exposure to CXCR4 antagonists results in mobilization of (hematopoietic) stem cells [8]. Rare individuals carrying a mutation that results in loss of the normal cytoplasmic tail, either by truncation or translational frame shift, which precludes desensitization following activation have a dominant syndrome characterized by warts, hypogammaglobulinemia, infections, and myelokathexis (retention of myeloid cells in the bone marrow) [9].

Keywords

Primordial Germ Cell Inverse Agonist Galactosidase Activity CXCR4 Antagonist Biologic Potency 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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Copyright information

© Birkhäuser Verlag Basel/Switzerland 2007

Authors and Affiliations

  • Zi-xuan Wang
    • 1
  • Hirokazu Tamamura
    • 2
  • Nicole Frilot
    • 1
  • James Broach
    • 3
  • Nobutaka Fujii
    • 2
  • Stephen C. Peiper
    • 1
  1. 1.Immunotherapy Center and Department of PathologyMedical College of GeorgiaAugustaUSA
  2. 2.Kyoto UniversityKyotoJapan
  3. 3.Princeton UniversityPrincetonUSA

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