Alternative titles; symbols
HGNC Approved Gene Symbol: SERPINB5
Cytogenetic location: 18q21.33 Genomic coordinates (GRCh38): 18:63,476,958-63,505,085 (from NCBI)
Zou et al. (1994) used subtractive hybridization and the 'differential display' method to identify candidate tumor suppressor genes that are defective in human breast carcinoma cells. These genes were identified initially by searching for mRNAs whose expression is reduced or absent in tumor cells compared with normal cells grown under similar conditions. Zou et al. (1994) reported the characteristics of one of the more than 30 genes so identified, a member of the serpin family of protease inhibitors which they termed maspin. A single 3.0-kb maspin mRNA was expressed in normal mammary epithelial cell strains, but not in most mammary tumor cell lines examined. Southern blot analysis of XbaI-restricted DNA from normal and tumor cells with a maspin cDNA probe revealed no gross structural alterations of the maspin gene in the tumor cells. This result suggested that the maspin gene is downregulated but not mutated in cancer cells. Transfection of mammary carcinoma cells with the maspin gene did not alter the growth properties of the cells in vitro, but reduced their ability to induce tumors and metastasize in nude mice and to invade through a basement membrane matrix in vitro. Analysis of human breast cancer specimens demonstrated that loss of maspin expression occurred most frequently in advanced cancers. These results supported the hypothesis that maspin functions as a tumor suppressor.
Ngamkitidechakul et al. (2001) determined that human corneal cells in the epithelium, endothelium, and stroma express maspin. They stated that corneal stromal cells are the first nonepithelial cells shown to synthesize maspin. They hypothesized that maspin might function within the cornea to regulate cell adhesion to extracellular matrix molecules and perhaps to regulate the migration of activated fibroblasts during corneal stromal wound healing.
Schneider et al. (1995) demonstrated that the maspin gene is located at 18q21.3 in a cluster of genes encoding members of the ovalbumin family of serine proteinase inhibitors. The others are plasminogen activator inhibitor type 2 (PAI2; 173390) and squamous cell carcinoma antigen-1 (SCCA1; 600517) and -2 (SCCA2; 600518). The 4 ovalbumin serine protease inhibitors (Ov-serpins) reside within a 300-kb region of 18q21.3. Their telomere-to-centromere order was PAI2--SCCA1--SCCA2--PI5. The transcriptional orientation of SCCA1 and SCCA2 was telomere to centromere and opposite to that of PAI2 and PI5. Schneider et al. (1995) localized maspin to band 18q21.3 using DNA from a chromosome 18 deletion panel of somatic cell hybrids and sublocalized the gene to the same YAC clone that contained SCCA1 and SCCA2 by PCR and pulsed field gel electrophoresis.
The nucleotide 5-methylcytosine is involved in processes crucial to mammalian development, such as X-chromosome inactivation and gene imprinting. In addition, cytosine methylation may be involved in the establishment and maintenance of cell type-specific expression of developmentally regulated genes; however, it is difficult to identify clear examples of such genes, particularly in humans. Futscher et al. (2002) provided evidence that cytosine methylation of the maspin gene promoter controls, in part, normal cell type-specific SERPINB5 expression. In normal cells expressing SERPINB5, the SERPINB5 promoter is unmethylated and the promoter region has acetylated histones and an accessible chromatin structure. In contrast, normal cells that do not express SERPINB5 have a completely methylated SERPINB5 promoter with hypoacetylated histones, an inaccessible chromatin structure, and a transcriptional repression that is relieved by inhibition of DNA methylation. These findings indicated that cytosine methylation is important in the establishment and maintenance of cell type-restricted gene expression.
Bass et al. (2002) characterized eukaryotic maspin and found that it had no protease inhibitory effect against any of the proteolytic systems tested. It did, however, inhibit the migration of both tumor and vascular smooth muscle cells. Bass et al. (2002) concluded that maspin is a noninhibitory serpin and that protease inhibition does not account for its activity as a tumor suppressor.
Maspin specifically inhibits prostate cancer-associated PLAU (191840) and prostate cancer cell invasion and motility in vitro. Cher et al. (2003) showed that maspin-expressing transfectant cells derived from a prostate cancer cell line were inhibited in in vitro extracellular matrix and collagen degradation assays. To test the effect of tumor-associated maspin on prostate cancer-induced bone matrix remodeling and tumor growth, Cher et al. (2003) injected maspin-transfected prostate cancer cells into human fetal bone fragments which were previously implanted in immunodeficient mice. These studies showed that maspin expression decreased tumor growth, reduced osteolysis, and decreased angiogenesis. The maspin-expressing tumors contained significant fibrosis and collagen staining, and exhibited a more glandular organization. These data represented evidence that maspin inhibits prostate cancer-induced bone matrix remodeling and induces prostate cancer glandular redifferentiation. These results support the working hypothesis that maspin exerts its tumor suppressive role, at least in part, by blocking the pericellular uPA system and suggest that maspin may offer an opportunity to improve therapeutic intervention of bone metastases.
Luo et al. (2007) examined IKK-alpha (CHUK; 600664) involvement in prostate cancer and its progression. They demonstrated that a mutation that prevents IKK-alpha activation slowed down prostate cancer growth and inhibited metastatogenesis in TRAMP mice, which express SV40 T antigen in the prostate epithelium. Decreased metastasis correlated with elevated expression of the metastasis suppressor Maspin, the ablation of which restored metastatic activity. IKK-alpha activation by RANK ligand (RANKL; 602642) inhibited Maspin expression in prostate epithelial cells, whereas repression of Maspin transcription required nuclear translocation of active IKK-alpha. The amount of active nuclear IKK-alpha in mouse and human prostate cancer correlated with metastatic progression, reduced Maspin expression, and infiltration of prostate tumors with RANKL-expressing inflammatory cells. Luo et al. (2007) proposed that tumor-infiltrating RANKL-expressing cells leads to nuclear IKK-alpha activation and inhibition of Maspin transcription, thereby promoting the metastatic phenotype.
Bass, R., Fernandez, A.-M. M., Ellis, V. Maspin inhibits cell migration in the absence of protease inhibitory activity. J. Biol. Chem. 277: 46845-46848, 2002. [PubMed: 12384513] [Full Text: https://doi.org/10.1074/jbc.C200532200]
Cher, M. L., Biliran, H. R., Jr., Bhagat, S., Meng, Y., Che, M., Lockett, J., Abrams, J., Fridman, R., Zachareas, M., Sheng, S. Maspin expression inhibits osteolysis, tumor growth, and angiogenesis in a model of prostate cancer bone metastasis. Proc. Nat. Acad. Sci. 100: 7847-7852, 2003. [PubMed: 12788977] [Full Text: https://doi.org/10.1073/pnas.1331360100]
Futscher, B. W., Oshiro, M. M., Wozniak, R. J., Holtan, N., Hanigan, C. L., Duan, H., Domann, F. E. Role for DNA methylation in the control of cell type-specific maspin expression. Nature Genet. 31: 175-179, 2002. [PubMed: 12021783] [Full Text: https://doi.org/10.1038/ng886]
Luo, J.-L., Tan, W., Ricono, J. M., Korchynskyi, O., Zhang, M., Gonias, S. L., Cheresh, D. A., Karin, M. Nuclear cytokine-activated IKK-alpha controls prostate cancer metastasis by repressing Maspin. Nature 446: 690-694, 2007. Note: Erratum: Nature 457: 920 only, 2009. [PubMed: 17377533] [Full Text: https://doi.org/10.1038/nature05656]
Miyake, H., Hara, I., Yamanaka, K., Arakawa, S., Kamidono, S. Elevation of urokinase-type plasminogen activator and its receptor densities as new predictors of disease progression and prognosis in men with prostate cancer. Int. J. Oncol. 14: 535-541, 1999. [PubMed: 10024688] [Full Text: https://doi.org/10.3892/ijo.14.3.535]
Ngamkitidechakul, C., Burke, J. M., O'Brien, W. J., Twining, S. S. Maspin: synthesis by human cornea and regulation of in vitro stromal cell adhesion to extracellular matrix. Invest. Ophthal. Vis. Sci. 42: 3135-3141, 2001. [PubMed: 11726614]
Schneider, S. S., Schick, C., Fish, K. E., Miller, E., Pena, J. C., Treter, S. D., Hui, S. M., Silverman, G. A. A serine proteinase inhibitor locus at 18q21.3 contains a tandem duplication of the human squamous cell carcinoma antigen gene. Proc. Nat. Acad. Sci. 92: 3147-3151, 1995. [PubMed: 7724531] [Full Text: https://doi.org/10.1073/pnas.92.8.3147]
Zou, Z., Anisowicz, A., Hendrix, M. J. C., Thor, A., Neveu, M., Sheng, S., Rafidi, K., Seftor, E., Sager, R. Maspin, a serpin with tumor-suppressing activity in human mammary epithelial cells. Science 263: 526-529, 1994. [PubMed: 8290962] [Full Text: https://doi.org/10.1126/science.8290962]