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Serpina1a  -  serine (or cysteine) peptidase inhibitor,...

Mus musculus

Synonyms: AAT, Aat-2, Aat2, Alpha-1 protease inhibitor 1, Alpha-1-antiproteinase, ...
 
 
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Disease relevance of Serpina1a

 

High impact information on Serpina1a

  • The PU.1 transcription factor is the product of the putative oncogene Spi-1 [6].
  • The p53 and Spi-1 genes were frequently aberrant in transplanted tumors and cell lines derived from them, but were not in primary leukemic spleens [7].
  • Using peritoneal infiltration models, we demonstrate that AAT decreases allogeneic fibroblast-elicited natural-killer-cell influx by 89%, CD3-positive cell influx by 44%, and thioglycolate-elicited neutrophil emigration by 66% [8].
  • For newly synthesized alpha1-antitrypsin (AAT), the modification of its asparagine-linked oligosaccharides by a slow-acting mannosidase partitions the misfolded monomer into the proteasomal degradation pathway [1].
  • Herein, we asked whether, and how, modification by endoplasmic reticulum mannosidase I (ERManI) contributes to the preferential selection of the misfolded AAT monomer for proteasomal degradation [1].
 

Chemical compound and disease context of Serpina1a

  • The rates of rearrangement of the Spi-1 (PU.1 ) oncogene by provirus integration and alteration of the p53 tumor-suppressor gene were the same in leukemia cell lines derived from folate-deficient mice as they were in cell lines from control mice [9].
  • In contrast to the results described for mouse erythroleukemia cells, DMSO did not markedly decrease the level of the Spi-1/PU.1 transcription factor [10].
  • Activities of the cytoplasmic and mitochondrial isozymes of aspartate aminotransferase (aspartate:2-oxoglutarate aminotransferase, EC 2.6.1.1, AAT) in transplantable mouse hepatomas BW7756 and H-4 are reduced when compared to normal adult liver [11].
 

Biological context of Serpina1a

  • Mice express at least seven closely related alpha(1)-PI isoforms, encoded by a family of genes clustered at the Spi1 locus on chromosome 12 [12].
  • The Mus musculus alpha 1-protease inhibitor gene cluster encodes five highly related proteins [13].
  • Adoptive transfer experiments demonstrated that AAT gene therapy attenuated cellular immunity associated with beta cell destruction [14].
  • Safety parameters will be measurement of changes in serum chemistries and hematology, urinalysis, pulmonary function testing, semen assay for vector genomes, immunologic response to AAT, and AAV, as well as reported subject history of any symptoms [2].
  • This study demonstrates that AAT gene therapy attenuates cell-mediated autoimmunity, alters the T cell receptor repertoire, and efficiently prevents type 1 diabetes in the NOD mouse model [14].
 

Anatomical context of Serpina1a

  • In addition, staining of endothelial cells with ATZ11 antibody in both M- and Z-AAT individuals shows that AAT attached to endothelial cells is in a polymerized form [15].
  • T cell receptor spectratyping indicated that AAT gene therapy altered T cell repertoire diversity in splenocytes from NOD mice [14].
  • Retinoic acid does not affect the angiogenic capacity of the VYS mesenchyme but destroys lysosomes, which release hydrolytic enzymes, leading to degradation of AAT in the endodermal cells and then digestion of endocytosed bFGF [16].
  • The peripheral components of PI1 and PI2 appear to be localized at nuclear pores and the nuclear envelope, respectively [17].
  • Thin sections of mouse 3T3 fibroblast nuclei labelled by immunoperoxidase with anti-nuclear antibodies I1, PI1, PI2, anti-peripherin, -lamin, and -centromere have been examined in the electron microscope [17].
 

Associations of Serpina1a with chemical compounds

 

Other interactions of Serpina1a

 

Analytical, diagnostic and therapeutic context of Serpina1a

  • In light of the established safety record and the nondiabetogenic potential of AAT, these data suggest that AAT may be beneficial as adjunctive therapy in patients undergoing islet transplantation [8].
  • Using electrophoresis, Western blotting, and ELISA procedures, we have shown in the present study that this monoclonal antibody specifically detects a conformation-dependent neoepitope on both polymerized and elastase-complexed molecular forms of AAT [15].
  • These results strongly suggest that rAAV1-mediated AAT gene therapy may be useful as a novel approach to prevent type 1 diabetes [14].
  • The efficiency of both anionic and cationic liposomes as vectors for in vivo human alpha1-antitrypsin (AAT) gene transfer was studied in mice with and without an associated partial hepatectomy [18].
  • Electrophoretic mobility shift assays and DNase I protection analyses revealed that FP I was bound by the transcription factor PU.1/Spi-1 [27].

References

  1. Elucidation of the molecular logic by which misfolded alpha 1-antitrypsin is preferentially selected for degradation. Wu, Y., Swulius, M.T., Moremen, K.W., Sifers, R.N. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  2. Phase I trial of intramuscular injection of a recombinant adeno-associated virus alpha 1-antitrypsin (rAAV2-CB-hAAT) gene vector to AAT-deficient adults. Flotte, T.R., Brantly, M.L., Spencer, L.T., Byrne, B.J., Spencer, C.T., Baker, D.J., Humphries, M. Hum. Gene Ther. (2004) [Pubmed]
  3. Efficient hepatic delivery and expression from a recombinant adeno-associated virus 8 pseudotyped alpha1-antitrypsin vector. Conlon, T.J., Cossette, T., Erger, K., Choi, Y.K., Clarke, T., Scott-Jorgensen, M., Song, S., Campbell-Thompson, M., Crawford, J., Flotte, T.R. Mol. Ther. (2005) [Pubmed]
  4. Epstein-Barr virus/human vector provides high-level, long-term expression of alpha1-antitrypsin in mice. Stoll, S.M., Sclimenti, C.R., Baba, E.J., Meuse, L., Kay, M.A., Calos, M.P. Mol. Ther. (2001) [Pubmed]
  5. Spi-1/PU.1 transgenic mice develop multistep erythroleukemias. Moreau-Gachelin, F., Wendling, F., Molina, T., Denis, N., Titeux, M., Grimber, G., Briand, P., Vainchenker, W., Tavitian, A. Mol. Cell. Biol. (1996) [Pubmed]
  6. The PU.1 transcription factor is the product of the putative oncogene Spi-1. Goebl, M.K. Cell (1990) [Pubmed]
  7. Env-derived gp55 gene of Friend spleen focus-forming virus specifically induces neoplastic proliferation of erythroid progenitor cells. Aizawa, S., Suda, Y., Furuta, Y., Yagi, T., Takeda, N., Watanabe, N., Nagayoshi, M., Ikawa, Y. EMBO J. (1990) [Pubmed]
  8. Alpha1-antitrypsin monotherapy prolongs islet allograft survival in mice. Lewis, E.C., Shapiro, L., Bowers, O.J., Dinarello, C.A. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  9. Folate deficiency delays the onset but increases the incidence of leukemia in Friend virus-infected mice. Koury, M.J., Park, D.J., Martincic, D., Horne, D.W., Kravtsov, V., Whitlock, J.A., del Pilar Aguinaga, M., Kopsombut, P. Blood (1997) [Pubmed]
  10. DMSO reduces CSF-1 receptor levels and causes apoptosis in v-myc immortalized mouse macrophages. Marthyn, P., Beuscart, A., Coll, J., Moreau-Gachelin, F., Righi, M. Exp. Cell Res. (1998) [Pubmed]
  11. Turnover of cytoplasmic and mitochondrial aspartate aminotransferase isozymes in mouse liver and transplantable hepatomas. Shaffer, J.B., Felder, M.R. Arch. Biochem. Biophys. (1983) [Pubmed]
  12. Functional diversification during evolution of the murine alpha(1)-proteinase inhibitor family: role of the hypervariable reactive center loop. Barbour, K.W., Goodwin, R.L., Guillonneau, F., Wang, Y., Baumann, H., Berger, F.G. Mol. Biol. Evol. (2002) [Pubmed]
  13. The expression and characterization of five recombinant murine alpha 1-protease inhibitor proteins. Paterson, T., Moore, S. Biochem. Biophys. Res. Commun. (1996) [Pubmed]
  14. Alpha1-antitrypsin gene therapy modulates cellular immunity and efficiently prevents type 1 diabetes in nonobese diabetic mice. Lu, Y., Tang, M., Wasserfall, C., Kou, Z., Campbell-Thompson, M., Gardemann, T., Crawford, J., Atkinson, M., Song, S. Hum. Gene Ther. (2006) [Pubmed]
  15. Detection of circulating and endothelial cell polymers of Z and wild type alpha 1-antitrypsin by a monoclonal antibody. Janciauskiene, S., Dominaitiene, R., Sternby, N.H., Piitulainen, E., Eriksson, S. J. Biol. Chem. (2002) [Pubmed]
  16. Induction of avascular yolk sac due to reduction of basic fibroblast growth factor by retinoic acid in mice. Yasuda, Y., Nishi, N., Takahashi, J.A., Konishi, H., Ohara, I., Fujita, H., Ohta, M., Itoh, N., Hatanaka, M., Tanimura, T. Dev. Biol. (1992) [Pubmed]
  17. Ultrastructural localization of nuclear antigens during interphase in mouse 3T3 fibroblasts. Chaly, N., St Aubin, G., Brown, D.L. Biochem. Cell Biol. (1989) [Pubmed]
  18. Long-term expression of the human alpha1-antitrypsin gene in mice employing anionic and cationic liposome vectors. Crepso, J., Blaya, C., Crespo, A., Aliño, S.F. Biochem. Pharmacol. (1996) [Pubmed]
  19. In vitro selection of lymphocytic choriomeningitis virus escape mutants by cytotoxic T lymphocytes. Aebischer, T., Moskophidis, D., Rohrer, U.H., Zinkernagel, R.M., Hengartner, H. Proc. Natl. Acad. Sci. U.S.A. (1991) [Pubmed]
  20. Overexpression of PU.1 induces growth and differentiation inhibition and apoptotic cell death in murine erythroleukemia cells. Yamada, T., Kondoh, N., Matsumoto, M., Yoshida, M., Maekawa, A., Oikawa, T. Blood (1997) [Pubmed]
  21. Developmental expression, cellular localization, and testosterone regulation of alpha 1-antitrypsin in Mus caroli kidney. Latimer, J.J., Berger, F.G., Baumann, H. J. Biol. Chem. (1987) [Pubmed]
  22. Spi-1 and Spi-B control the expression of the Grap2 gene in B cells. Garrett-Sinha, L.A., Hou, P., Wang, D., Grabiner, B., Araujo, E., Rao, S., Yun, T.J., Clark, E.A., Simon, M.C., Clark, M.R. Gene (2005) [Pubmed]
  23. Kit-Activating Mutations in AML: Lessons from PU.1-Induced Murine Erythroleukemia. Cozma, D., Thomas-Tikhonenko, A. Cancer Biol. Ther. (2006) [Pubmed]
  24. Neutrophil lysosomal dysfunctions in mutant C57 Bl/6J mice: interstrain variations in content of lysosomal elastase, cathepsin G and their inhibitors. Gardi, C., Cavarra, E., Calzoni, P., Marcolongo, P., de Santi, M., Martorana, P.A., Lungarella, G. Biochem. J. (1994) [Pubmed]
  25. Molecular cloning and characterization of rat contrapsin-like protease inhibitor and related proteins. Ohkubo, K., Ogata, S., Misumi, Y., Takami, N., Ikehara, Y. J. Biochem. (1991) [Pubmed]
  26. Detection of alpha 2-macroglobulin, alpha 1-protease inhibitor, and neutral protease-antiprotease complexes within liver granulomas of Schistosoma mansoni-infected mice. Truden, J.L., Boros, D.L. Am. J. Pathol. (1988) [Pubmed]
  27. PU.1/Spi-1 is essential for the B cell-specific activity of the mouse CD72 promoter. Ying, H., Chang, J.F., Parnes, J.R. J. Immunol. (1998) [Pubmed]
 
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