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

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.

Pubmed ID: 12816952

Authors

  • Rishi AK
  • Zhang L
  • Boyanapalli M
  • Wali A
  • Mohammad RM
  • Yu Y
  • Fontana JA
  • Hatfield JS
  • Dawson MI
  • Majumdar AP
  • Reichert U

Journal

The Journal of biological chemistry

Publication Data

August 29, 2003

Associated Grants

  • Agency: NCI NIH HHS, Id: CA51993

Mesh Terms

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