Accession Number : ADA354376


Title :   Characterization of Breast Cancer Cell Death induced by interferons and Retinoids.


Descriptive Note : Annual rept. 1 Jul 97-30 Jun 98


Corporate Author : MARYLAND UNIV BALTIMORE


Personal Author(s) : Kalvakolanu, Dhan ; Hofmann, Edward


Full Text : http://www.dtic.mil/get-tr-doc/pdf?AD=ADA354376


Report Date : JUL 1998


Pagination or Media Count : 17


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 systems we have shown earlier that IFNBeta/RA combination causes cell death of human breast carcinoma cells. Since we could not find a correlation between expression of known regulators and cell death, we employed the antisense technical knock-out strategy to isolate genes that participate in IFN/RA induced pathways. We prepared total cell cDNA libraries from breast tumor cells treated with IFN/RA combination and cloned the inserts in antisense orientation into the episomal vector pTKO1. Following transfection of these libraries the breast tumor cells were selected for resistance to IFN/RA induced cell death. Using this technique we have isolated several candidate genes termed Genes associated with Retinoid-IFN Induced Mortality (GRIM). In this report, we have identified one of these genes, GRIM-12. Sequence analysis revealed that GRIM-12 is identical to human thioredoxin reductase (TR). IFN/RA combination stimulates the post-transcriptional expression of GRIM-l2. The enzymatic activity of TR was essential for mediating cell death. Dominant negative mutants have been made to characterize this gene further. Another gene, GRIM-i, has been identified as a novel sequence. Northern analysis demonstrated the IFN/RA combination induces two GRIM-1transcrints. cDNA gamma phage libraries were screened in attempt to clone the full length cDNA.


Descriptors :   *NEOPLASMS , *INTERFERON , *DEATH , *CELLS(BIOLOGY) , *BREAST CANCER , HUMANS , ENZYMES , MUTATIONS , IN VITRO ANALYSIS , SEQUENCES , GAMMA RAYS , GENES , CLONES , NORTH(DIRECTION) , MICE , LIBRARIES , ACIDS , MAMMARY GLANDS , VITAMIN A , BACTERIOPHAGES.


Subject Categories : BIOCHEMISRTY
      ANATOMY AND PHYSIOLOGY
      MEDICINE AND MEDICAL RESEARCH


Distribution Statement : APPROVED FOR PUBLIC RELEASE