Characterization of Breast Cancer Cell Death Induced by Interferons and Retinoids

Abstract

Interferons (IFNs) and retinoic acid (RA) are potent biological response modifiers that inhibit transformed cell growth. In tumor cells resistant to either IFN or RA, combination of both agents causes stronger growth inhibition. Using athymic nude mouse models and in vitro assays we have previously shown that IFN-beta/RA combination causes death of human breast carcinoma cells. To identify genes that participate in IFN-beta/RA induced death pathways, we employed a genetic strategy called Suppression of Mortality by Antisense-Rescue Technique (SMART). Rescue of genes was possible by positive growth selection of cells treated with IFN-beta/RA after transfection with antisense cDNA expression libraries. Using this system we have isolated several candidate genes termed Genes associated with Retinoid-Interferon induced Mortality (GRIM). Previously, we have demonstrated that GRIM-12 is identical to human thioredoxin reductase (TR). In this report we demonstrate that GRIM-12 overexpression suppresses cell growth. Growth suppression is mediated by increased enzyme activity and is enhanced by IFN-beta/RA combination. Furthermore, we have characterized an interface domain (ID) that inhibits the growth suppressive effects of IFN-beta/RA combination but not other activators of growth suppression. Interference with TR enzyme activity by ID expression led to growth promotion in the presence of IFN-beta/RA combination. We have demonstrated that this domain is able to associate with lull-length GRIM-12 in vitro. Thus, dimerization may be important for GRIM-12 mediated growth suppression. We have confirmed that GRIM-1 is a novel gene. In this report we use 5'RACE to isolate a full-length cDNA. Northern analysis revealed that many GRIM-1 transcripts are expressed in many human and mouse tissues in a tissue specific manner. GRIM-1 is able to encode three proteins in vitro.

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Document Details

Document Type
Technical Report
Publication Date
Jul 01, 1999
Accession Number
ADB253635

Entities

People

  • Dhan Kalvakolanu
  • Edward Hofmann

Organizations

  • University of Maryland, Baltimore

Tags

DTIC Thesaurus Topics

  • Breast Cancer
  • Cell Line
  • Cell Physiological Processes
  • Cells
  • Chemical Synthesis
  • Chemistry
  • Fungi
  • Lymphatic System
  • Lymphocytes
  • Programmed Cell Death
  • Proteins
  • Tissues
  • Tumor Cell Line

Fields of Study

  • Biology
  • Medicine

Readers

  • Materials Science (Mechanical Engineering).
  • Molecular Biology and Genetics
  • Oncology (Cancer Research).

Technology Areas

  • Biotechnology
  • Biotechnology - Cancer Biotech