Maspin polymorphism associated with apoptosis susceptibility and in vivo tumorigenesis.
Maspin is a tumor suppressor protein that stimulates apoptosis and inhibits motility, invasion and cancer metastasis. We report on a previously uncharacterized Pro/Ser (C to T) polymorphism at amino acid 176 of the human maspin protein. We analyzed the maspin mutation in 17 cancer cell lines and 36 cancer tissues. Association of polymorphic variants on apoptosis, colony formation and in vivo tumor formation was evaluated. Mutant maspin was found to be frequently expressed in gastric cancer (32/36, 89%). According to predicted maspin tertiary structure, the polymorphic residue is located on the surface of the protein proximal to the reactive site loop domain, and thus may significantly affect the protein interactions of maspin. Stable expression of the Pro and Ser forms of maspin in lung cancer cells revealed that cells expressing Ser176 maspin showed significantly decreased apoptosis and increased colony formation compared with those expressing Pro176 maspin. In a mouse model, cells expressing Ser176 maspin showed a higher rate of tumor formation in vivo than those harboring Pro176 maspin. Therefore, P176S (C526T) substitution of maspin may result in a partial loss of the tumor suppressor function of this protein, contributing to decreased susceptibility to apoptosis and malignant progression.
Jang
Hye-Lim
HL
Cancer Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-710, Korea.
Nam
Eunsook
E
Lee
Kon Ho
KH
Yeom
Seonyong
S
Son
Hee Jung
HJ
Park
Chaehwa
C
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D004198:Disease Susceptibility; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D009154:Mutation / Q000235:genetics; D011110:Polymorphism, Genetic / Q000235:genetics*; D017434:Protein Structure, Tertiary; D015843:Serpins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
C085344:SERPIN-B5; D015843:Serpins