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.
Rishi
Arun K
AK
Veterans Affairs Medical Center, Department of Internal Medicine and Karmanos Cancer Institute, Wayne State University, Detroit, Michigan 48201, USA. Rishia@Karmanos.org
Zhang
Liyue
L
Boyanapalli
Madanamohan
M
Wali
Anil
A
Mohammad
Ramzi M
RM
Yu
Yingjie
Y
Fontana
Joseph A
JA
Hatfield
James S
JS
Dawson
Marcia I
MI
Majumdar
Adhip P N
AP
Reichert
Uwe
U
D020413:3' Untranslated Regions; D020121:5' Untranslated Regions; D000970:Antineoplastic Agents / Q000378:metabolism*; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D015153:Blotting, Western; D018797:Cell Cycle Proteins / Q000737:chemistry* / Q000302:isolation & purification / Q000378:metabolism; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D003001:Cloning, Molecular; D004396:Coloring Agents / Q000494:pharmacology; D018076:DNA, Complementary / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology; D004591:Electrophoresis, Polyacrylamide Gel; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D006801:Humans; D008954:Models, Biological; D009375:Neoplasms, Glandular and Epithelial / Q000378:metabolism; D009841:Oligonucleotides / Q000737:chemistry; D016376:Oligonucleotides, Antisense / Q000737:chemistry; D016366:Open Reading Frames; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D011485:Protein Binding; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D012176:Retinoids / Q000378:metabolism* / Q000502:physiology*; D012190:Retroviridae / Q000235:genetics; D013778:Tetrazolium Salts / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D013997:Time Factors; D014407:Tumor Cells, Cultured
D020413:3' Untranslated Regions; D020121:5' Untranslated Regions; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C477529:CCAR1 protein, human; C099555:CD 437; D018797:Cell Cycle Proteins; D004396:Coloring Agents; D018076:DNA, Complementary; D009841:Oligonucleotides; D016376:Oligonucleotides, Antisense; D016271:Proto-Oncogene Proteins c-myc; D012176:Retinoids; D013778:Tetrazolium Salts; D013844:Thiazoles; D004317:Doxorubicin; C022616:thiazolyl blue