Stomach cancer-derived del223V-226L mutation of the STCH gene causes loss of sensitization to TRAIL-mediated apoptosis.
The stress 70 protein chaperone (STCH), a member of the heat shock protein 70 (HSP70) superfamily, is a microsomal protein that contains a N-terminal ATPase domain but lacks a C-terminal protein binding domain. Although cell-protective functions of HSP70 members are well characterized, the biological relevance of STCH remains unclear. We previously identified STCH as a candidate gene for susceptibility to stomach cancer by genetic analyses. In this study, we searched somatic mutations of STCH in human stomach cancer and identified the 668del12bp mutation in exon 4, resulting in a four amino acid deletion (del223V-226L) in the conserved ATP-binding domain. In vitro binding assays revealed that this mutant lacks ATP-binding activity. Overexpression of wild-type STCH sensitized cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced cell death, whereas del223V-226L mutant did not show any effect. These results suggest that STCH has a role in cell survival via modulation of the TRAIL-mediated cell death pathway.
Yamagata
Nobushige
N
Department of Molecular Genetics, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
Furuno
Kenji
K
Sonoda
Miki
M
Sugimura
Haruhiko
H
Yamamoto
Ken
K
D000255:Adenosine Triphosphate / Q000378:metabolism; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D017209:Apoptosis / Q000235:genetics*; D002470:Cell Survival / Q000235:genetics; D005260:Female; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D017384:Sequence Deletion; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism / Q000494:pharmacology
D018840:HSP70 Heat-Shock Proteins; C086345:HSPA13 protein, human; D053221:TNF-Related Apoptosis-Inducing Ligand; D000255:Adenosine Triphosphate