A novel isoform of TUCAN is overexpressed in human cancer tissues and suppresses both caspase-8- and caspase-9-mediated apoptosis.
Caspase-associated recruitment domains (CARD) are protein-protein interaction modules found extensively in proteins that play important roles in apoptosis. One of the CARD-containing proteins, TUCAN (CARD8), was reported previously as an antiapoptotic protein with a molecular weight of 48 kDa, which was up-regulated in colon cancer cells. We identified a novel isoform of TUCAN with a molecular weight of 54 kDa. The new variant of TUCAN, termed TUCAN-54, was expressed in gastric, colon, and breast cancer tissues but was barely detected in normal noncancerous tissues, whereas 48-kDa TUCAN was detected in tumor tissues and noncancerous tissues. To know the function of TUCAN-54 in the apoptosis of cancer cells, TUCAN-54 was overexpressed in tumor cells by gene transfection. Its overexpression inhibited pro-caspase-9 activation, leading to the suppression of the cell death induced by a protein kinase inhibitor, staurosporine, or a chemotherapeutic reagent, etoposide (VP-16). In contrast, specific small interfering RNA-mediated suppression of TUCAN-54 expression in tumor cells increased the VP-16-induced cell death rate, indicating that expression of TUCAN-54 might be associated with chemoresistance of tumor cells. In addition, it inhibited caspase-8 activation as well, thereby suppressing Fas-induced cell death. It was revealed that Fas-associated death domain was physically associated with TUCAN-54 but not with 48-kDa TUCAN. Thus, TUCAN-54 might be a novel tumor-specific antiapoptotic molecule expressed in a variety of human cancer tissues, which might aggravate malignant potential of cancer cells, such as chemoresistance and immunoresistance.
Yamamoto
Masaaki
M
Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan.
Torigoe
Toshihiko
T
Kamiguchi
Kenjiro
K
Hirohashi
Yoshihiko
Y
Nakanishi
Katsuya
K
Nabeta
Chika
C
Asanuma
Hiroko
H
Tsuruma
Tetsuhiro
T
Sato
Takashi
T
Hata
Fumitake
F
Ohmura
Tousei
T
Yamaguchi
Koji
K
Kurotaki
Takehiro
T
Hirata
Koichi
K
Sato
Noriyuki
N
D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000328:Adult; D000595:Amino Acid Sequence; D017209:Apoptosis / Q000502:physiology*; D053468:CARD Signaling Adaptor Proteins; D053181:Caspase 8; D053453:Caspase 9; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation; D005047:Etoposide / Q000494:pharmacology; D053200:Fas-Associated Death Domain Protein; D006801:Humans; D019169:Jurkat Cells; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D009369:Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D020033:Protein Isoforms; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D019311:Staurosporine / Q000494:pharmacology; D014162:Transfection; D019014:fas Receptor / Q000502:physiology
D048868:Adaptor Proteins, Signal Transducing; D053468:CARD Signaling Adaptor Proteins; C455623:CARD8 protein, human; D061945:Caspase Inhibitors; C505533:FADD protein, human; D053200:Fas-Associated Death Domain Protein; D009363:Neoplasm Proteins; D020033:Protein Isoforms; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D019014:fas Receptor; D005047:Etoposide; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; D019311:Staurosporine