A novel isoform of TUCAN is overexpressed in human cancer tissues and suppresses both caspase-8- and caspase-9-mediated apoptosis.

Abstract

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.

• Authors: Masaaki Yamamoto, Toshihiko Torigoe, Kenjiro Kamiguchi, Yoshihiko Hirohashi, Katsuya Nakanishi, Chika Nabeta, Hiroko Asanuma, Tetsuhiro Tsuruma, Takashi Sato, Fumitake Hata, Tousei Ohmura, Koji Yamaguchi, Takehiro Kurotaki, Koichi Hirata, Noriyuki Sato
• Journal: Cancer research (Cancer Res) Vol. 65 Issue 19 Pg. 8706-14 (Oct 01 2005) ISSN: 0008-5472 [Print] United States
• PMID: 16204039 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adaptor Proteins, Signal Transducing
• CARD Signaling Adaptor Proteins
• CARD8 protein, human
• Caspase Inhibitors
• FADD protein, human
• Fas-Associated Death Domain Protein
• Neoplasm Proteins
• Protein Isoforms
• RNA, Messenger
• RNA, Small Interfering
• fas Receptor
• Etoposide
• CASP8 protein, human
• CASP9 protein, human
• Caspase 8
• Caspase 9
• Caspases
• Staurosporine

Topics

• Adaptor Proteins, Signal Transducing (biosynthesis, genetics, metabolism, physiology)
• Adult
• Amino Acid Sequence
• Apoptosis (physiology)
• CARD Signaling Adaptor Proteins
• Caspase 8
• Caspase 9
• Caspase Inhibitors
• Caspases (metabolism)
• Cell Line, Tumor
• Down-Regulation
• Drug Resistance, Neoplasm
• Enzyme Activation
• Etoposide (pharmacology)
• Fas-Associated Death Domain Protein
• Humans
• Jurkat Cells
• Molecular Sequence Data
• Neoplasm Proteins (biosynthesis, genetics, physiology)
• Neoplasms (enzymology, genetics, metabolism, pathology)
• Protein Isoforms
• Protein Structure, Tertiary
• RNA, Messenger (biosynthesis, genetics)
• RNA, Small Interfering (genetics)
• Staurosporine (pharmacology)
• Transfection
• fas Receptor (physiology)