Maspin (mammary serine protease inhibitor) is a protein that in humans is encoded by the SERPINB5gene.[5] This protein belongs to the serpin (serine protease inhibitor) superfamily.[5]SERPINB5 was originally reported to function as a tumor suppressor gene in epithelial cells, suppressing the ability of cancer cells to invade and metastasize to other tissues.[6] Furthermore, and consistent with an important biological function, Maspin knockout mice were reported to be non-viable, dying in early embryogenesis.[7] However, a subsequent study using viral transduction as a method of gene transfer (rather than single cell cloning) was not able to reproduce the original findings and found no role for maspin in tumour biology.[8] Furthermore, the latter study demonstrated that maspin knockout mice are viable and display no obvious phenotype.[8] These data are consistent with the observation that maspin is not expressed in early embryogenesis.[8] The precise molecular function of maspin is thus currently unknown.
Maspin is a member of the serpin superfamily of serine protease inhibitors.[5] The primary function of most members of this family is to regulate the breakdown of proteins by inhibiting the catalytic activity of proteinases. Through this mechanism of action, serpins regulate a number of cellular processes including phagocytosis, coagulation, and fibrinolysis.[9]
Serpins have a complex structure, a key component of which is the reactive site loop, RSL.[10] Inhibitory serpins transition between a stress and relaxed stage. The catalytic serine residue in the protease target attacks the stressed conformation of the RSL loop to form an acyl intermediate. The loop then undergoes a conformational change to the relaxed state irreversibly trapping the protease in an inactive state. Hence the serpin functions as a suicide inhibitor of the protease.[11] This transition does not occur in serpins that lack inhibitory activity.[10]
Function
Given its original reported role in cancer biology,[6] numerous studies have investigated a role for maspin in tumour metastasis.[12] However, to date no detailed molecular mechanism for maspin function in cell proliferation or tumour biology has been comprehensively described. Further, it is suggested that original reports of maspin as a tumor suppressor may reflect clonal artefacts rather than true maspin function.[8] Importantly, and in contrast to original reports, maspin knockout mice are viable, displaying no overt phenotype in the absence of suitable biological or environmental challenge.[8] Accordingly, the molecular function of maspin remains unclear.
From a structural perspective, maspin is a non-inhibitory and obligate intracellular member of the serpin superfamily.[13] Specifically, its RSL does not transition between a stressed and relaxed state following proteolytic cleavage.[14] This region is also shorter than the RSL loop in other serpins. Accordingly, in the absence of an obvious protease-related function, other targets of maspin have been suggested. For example, rather than being a protease inhibitor, maspin is proposed to function as an inhibitor of histone deacetylase 1 (HDAC1).[10][15]
Clinical significance
A comprehensive analysis of maspin expression in breast cancer revealed no significant correlation between maspin expression and overall survival, distant metastasis-free survival or recurrence-free survival.[8] Changes in maspin expression may, however, reflect the expression status of the known tumour suppressor PHLPP1.[8]
1 2 Zou Z, Anisowicz A, Hendrix MJ, Thor A, Neveu M, Sheng S, Rafidi K, Seftor E, Sager R (1994). "Maspin, a serpin with tumor-suppressing activity in human mammary epithelial cells". Science. 263 (5146): 526–9. Bibcode:1994Sci...263..526Z. doi:10.1126/science.8290962. PMID8290962.
↑ Gao F, Shi H, Daughty C, Cella N, Zhang M (2004). "Maspin plays an essential role in early embryonic development". Development. 131 (7): 1479–89. doi:10.1242/dev.01048. PMID14985257. S2CID10572194.
Pemberton PA, Tipton AR, Pavloff N, etal. (1998). "Maspin is an intracellular serpin that partitions into secretory vesicles and is present at the cell surface". J. Histochem. Cytochem. 45 (12): 1697–706. doi:10.1177/002215549704501213. PMID9389773. S2CID23938193.
Xia W, Lau YK, Hu MC, etal. (2000). "High tumoral maspin expression is associated with improved survival of patients with oral squamous cell carcinoma". Oncogene. 19 (20): 2398–403. doi:10.1038/sj.onc.1203535. PMID10828881. S2CID9319721.
Biliran H, Sheng S (2002). "Pleiotrophic inhibition of pericellular urokinase-type plasminogen activator system by endogenous tumor suppressive maspin". Cancer Res. 61 (24): 8676–82. PMID11751384.
Dokras A, Gardner LM, Kirschmann DA, etal. (2002). "The tumour suppressor gene maspin is differentially regulated in cytotrophoblasts during human placental development". Placenta. 23 (4): 274–80. doi:10.1053/plac.2001.0784. PMID11969337.
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