HRI is necessary for Regulation of Globin Translation and Survival of Erythroid Precursors in Iron-Deficiency

Reviewer: Walter F. Sall, MD
The Abramson Cancer Center of the University of Pennsylvania
Ultima Vez Modificado: 9 de diciembre del 2001

Share article


English

Presenter: An-Ping Han
Presenter's Affiliation: MIT
Type of Session: Plenary

Background

  • The balanced production of heme and globin chains during erythroid cell development results in the production of 250 million hemoglobin molecules per red blood cell. The production of globin chains is exquisitely regulated to match cellular iron stores, preventing excess globin chain production which can lead to chain precipitation and cell death.
  • In iron deficient states, globin chain production is down-regulated by mechanisms that have been poorly characterized.
  • Heme-regulated translational inhibitor (HRI) is a protein highly expressed in erythroid cells. Its tyrosine kinase activity is known to downregulate protein translation. It is hypothesized that HRI may act as a sensor of heme levels balancing globin chain production with intracellular heme concentration.
  • The physiologic function of HRI was evaluated in this study utilizing HRI knockout mice

    Materials and Methods

  • HRI knockout mice were generated for this study. These are viable and fertile mice with normal baseline red cell characteristics.
  • Mice were subjected to an iron deficient diet to assess red cell response.
  • Some mice were treated with phenylhydrazine to test the red cell response to oxidative stress.

    Results

  • On iron deficient diets, wild type mice developed the expected microcytic, hypochromic anemia while knockout mice developed an odd normocytic, hyperchromic anemia with an enlarged spleen, erythroid hyperplasia and increased apoptosis of erythroid precursors.
  • Heme-independent protein synthesis occurred in HRI knockout mice.
  • Precipitation of globin chains, similar to that seen in beta thalassemia patients, occurred in HRI knockout mice.
  • Phenylhydrazine induced hemolysis is lethal to HRI knockout mice but not wild type mice.

    Author's Conclusions

  • Phenylhydrazine testing shows that HRI negative red cells are unable to cope with oxidative stress.
  • The absence of HRI mediated control of globin chain synthesis led to a disregulation of the mechanism by which red cells balance heme and globin production. HRI funtions to protect red cells during period of iron deficiency.
  • HRI is responsible for the microcytic and hypochromic phenotype of iron deficiency.
  • HRI deficiency has not been found in any human disease.

    Clinical/Scientific Implications
    This study presents novel data regarding the molecular control mechanisms responsible for the exquisite control of globin chain synthesis. Though this gene has not been implicated in any human disease, further research may provide breakthroughs applicable to the treatment of thalassemia and other diseases of disordered globin synthesis.

    Oncolink's ASH Coverage made possible by an unrestricted Educational Grant from Amgen.

    English

  • I Wish You Knew

    How cancer patients have changed my life

    View More



    Blogs and Web Chats

    OncoLink Blogs give our readers a chance to react to and comment on key cancer news topics and provides a forum for OncoLink Experts and readers to share opinions and learn from each other.




    OncoLink OncoPilot

    Frente a un nuevo diagnóstico de cáncer o de cambiar el curso de su tratamiento actual? Deje que nuestro personal de enfermería cáncer que ayudan a pasar!

    Más información