Identification and characterization of a cell cycle and apoptosis regulatory protein-1 as a novel mediator of apoptosis signaling by retinoid CD437

J Biol Chem. 2003 Aug 29;278(35):33422-35. doi: 10.1074/jbc.M303173200. Epub 2003 Jun 18.

Abstract

CD437, a novel retinoid, causes cell cycle arrest and apoptosis in a number of cancer cells including human breast carcinoma (HBC) by utilizing an undefined retinoic acid receptor/retinoid X receptor-independent mechanism. To delineate mediators of CD437 signaling, we utilized a random antisense-dependent functional knockout genetic approach. We identified a cDNA that encodes approximately 130-kDa HBC cell perinuclear protein (termed CARP-1). Treatments with CD437 or chemotherapeutic agent adriamycin, as well as serum deprivation of HBC cells, stimulate CARP-1 expression. Reduced levels of CARP-1 result in inhibition of apoptosis by CD437 or adriamycin, whereas increased expression of CARP-1 causes elevated levels of cyclin-dependent kinase inhibitor p21WAF1/CIP1 and apoptosis. CARP-1 interacts with 14-3-3 protein as well as causes reduced expression of cell cycle regulatory genes including c-Myc and cyclin B1. Loss of c-Myc sensitizes cells to apoptosis by CARP-1, whereas expression of c-Myc or 14-3-3 inhibits CARP-1-dependent apoptosis. Thus, apoptosis induction by CARP-1 involves sequestration of 14-3-3 and CARP-1-mediated altered expression of multiple cell cycle regulatory genes. Identification of CARP-1 as a key mediator of signaling by CD437 or adriamycin allows for delineation of pathways that, in turn, may prove beneficial for design and targeting of novel antitumor agents.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 3' Untranslated Regions
  • 5' Untranslated Regions
  • Antineoplastic Agents / metabolism*
  • Apoptosis Regulatory Proteins
  • Apoptosis*
  • Blotting, Western
  • Cell Cycle Proteins / chemistry*
  • Cell Cycle Proteins / isolation & purification
  • Cell Cycle Proteins / metabolism
  • Cell Line
  • Cell Nucleus / metabolism
  • Cloning, Molecular
  • Coloring Agents / pharmacology
  • DNA, Complementary / metabolism
  • Doxorubicin / pharmacology
  • Electrophoresis, Polyacrylamide Gel
  • Flow Cytometry
  • Gene Expression Regulation
  • Humans
  • Models, Biological
  • Neoplasms, Glandular and Epithelial / metabolism
  • Oligonucleotides / chemistry
  • Oligonucleotides, Antisense / chemistry
  • Open Reading Frames
  • Plasmids / metabolism
  • Precipitin Tests
  • Protein Binding
  • Proto-Oncogene Proteins c-myc / metabolism
  • Retinoids / metabolism*
  • Retinoids / physiology*
  • Retroviridae / genetics
  • Tetrazolium Salts / pharmacology
  • Thiazoles / pharmacology
  • Time Factors
  • Tumor Cells, Cultured

Substances

  • 3' Untranslated Regions
  • 5' Untranslated Regions
  • Antineoplastic Agents
  • Apoptosis Regulatory Proteins
  • CCAR1 protein, human
  • CD 437
  • Cell Cycle Proteins
  • Coloring Agents
  • DNA, Complementary
  • Oligonucleotides
  • Oligonucleotides, Antisense
  • Proto-Oncogene Proteins c-myc
  • Retinoids
  • Tetrazolium Salts
  • Thiazoles
  • Doxorubicin
  • thiazolyl blue