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References

  1. Bard F, Malhotra V. 2006. The formation of TGN-to-plasmamembrane transport carriers. Annu. Rev. Cell Dev. Biol. 22:439-455.
    Pubmed CrossRef
  2. Becker E, Florin L, Pfizenmaier K, Kaufmann H. 2008. An XBP-1 dependent bottle-neck in production of IgG subtype antibodies in chemically defined serum-free Chinese hamster ovary (CHO) fed-batch processes. J. Biotechnol. 135: 217-223.
    Pubmed CrossRef
  3. Borth N, Mattanovich D, Kunert R, Katinger H. 2005. Effect of increased expression of protein disulfide isomerase and heavy chain binding protein on antibody secretion in a recombinant CHO cell line. Biotechnol. Prog. 21: 106-111.
    Pubmed CrossRef
  4. Butler M. 2005. Animal cell cultures: recent achievements and perspectives in the production of biopharmaceuticals. Appl. Microbiol. Biotechnol. 68: 283-291.
    Pubmed CrossRef
  5. Cacciatore JJ, Chasin LA, Leonard EF. 2010. Gene amplification and vector engineering to achieve rapid and high-level therapeutic protein production using the Dhfr-based CHO cell selection system. Biotechnol. Adv. 28: 673-681.
    Pubmed CrossRef
  6. Figueroa Jr B, Chen S, Oyler GA, Hardwick JM, Betenbaugh MJ. 2004. Aven and Bcl-xL enhance protection against apoptosis for mammalian cells exposed to various culture conditions. Biotechnol. Bioeng. 85: 589-600.
    Pubmed CrossRef
  7. Florin L, Pegel A, Becker E, Hausser A, Olayioye MA, Kaufmann H. 2009. Heterologous expression of the lipid transfer protein CERT increases therapeutic protein productivity of mammalian cells. J. Biotechnol. 141: 84-90.
    Pubmed CrossRef
  8. Fugmann T, Hausser A, Schoffler P, Schmid S, Pfizenmaier K, Olayioye MA. 2007. Regulation of secretory transport by protein kinase D-mediated phosphorylation of the ceramide transfer protein. J. Cell Biol. 178: 15-22.
    Pubmed CrossRef
  9. Fussenegger M, Schlatter S, Datwyler D, Mazur X, Bailey JE. 1998. Controlled proliferation by multigene metabolic engineering enhances the productivity of Chinese hamster ovary cells. Nat. Biotechnol. 16: 468-472.
    Pubmed CrossRef
  10. Geserick C, Bonarius HP, Kongerslev L, Hauser H, Mueller PP. 2000. Enhanced productivity during controlled proliferation of BHK cells in continuously perfused bioreactors. Biotechnol. Bioeng. 69: 266-274.
    CrossRef
  11. Hanada K, Kumagai K, Yasuda S, Miura Y, Kawano M, Fukasawa M, Nishijima M. 2003. Molecular machinery for non-vesicular trafficking of ceramide. Nature 426: 803-809.
    Pubmed CrossRef
  12. Jaluria P, Chu C, Betenbaugh M, Shiloach J. 2008. Cells by design: a mini-review of targeting cell engineering using DNA microarrays. Mol. Biotechnol. 39: 105-111.
    Pubmed CrossRef
  13. Jayapal KP, Wlaschin KF, Hu WS, Yap MGS. 2007. Recombinant protein therapeutics from CHO cells - 20 years and counting. Chem. Eng. Prog. 103: 40-47.
  14. Josse L, Smales CM, Tuite MF. 2012. Engineering the chaperone network of CHO cells for optimal recombinant protein production and authenticity. Methods Mol. Biol. 824:595-608.
    Pubmed CrossRef
  15. Khan SU, Schroder M. 2008. Engineering of chaperone systems and of the unfolded protein response. Cytotechnology 57: 207-231.
    Pubmed CrossRef
  16. Kim JY, Kim YG, Lee GM. 2012. CHO cells in biotechnology for production of recombinant proteins: current state and further potential. Appl. Microbiol. Biotechnol. 93: 917-930.
    Pubmed CrossRef
  17. Kim SH, Lee GM. 2007. Functional expression of human pyruvate carboxylase for reduced lactic acid formation of Chinese hamster ovary cells (DG44). Appl. Microbiol. Biotechnol. 76: 659-665.
    Pubmed CrossRef
  18. Kramer O, Klausing S, Noll T. 2010. Methods in mammalian cell line engineering: from random mutagenesis to sequencespecific approaches. Appl. Microbiol. Biotechnol. 88: 425-436.
    Pubmed CrossRef
  19. Ku SC, Ng DT, Yap MG, Chao SH. 2008. Effects of overexpression of X-box binding protein 1 on recombinant protein production in Chinese hamster ovary and NS0 myeloma cells. Biotechnol. Bioeng. 99: 155-164.
    Pubmed CrossRef
  20. Ku SC, Toh PC, Lee YY, Chusainow J, Yap MG, Chao SH. 2010. Regulation of XBP-1 signaling during transient and stable recombinant protein production in CHO cells. Biotechnol. Prog. 26: 517-526.
    Pubmed
  21. Lee AH, Iwakoshi NN, Glimcher LH. 2003. XBP-1 regulates a subset of endoplasmic reticulum resident chaperone genes in the unfolded protein response. Mol. Cell Biol. 23: 74487459.
    CrossRef
  22. Meents H, Enenkel B, Werner RG, Fussenegger M. 2002. p27Kip1-mediated controlled proliferation technology increases constitutive sICAM production in CHO-DUKX adapted for growth in suspension and serum-free media. Biotechnol. Bioeng. 79: 619-627.
    Pubmed CrossRef
  23. O’Callaghan PM, James DC. 2008. Systems biotechnology of mammalian cell factories. Brief. Funct. Genomic. Proteomic. 7:95-110.
    Pubmed CrossRef
  24. Ohya T, Hayashi T, Kiyama E, Nishii H, Miki H, Kobayashi K, et al. 2008. Improved production of recombinant human antithrombin III in Chinese hamster ovary cells by ATF4 overexpression. Biotechnol. Bioeng. 100: 317-324.
    Pubmed CrossRef
  25. Onitsuka M, Kim WD, Ozaki H, Kawaguchi A, Honda K, Kajiura H, et al. 2012. Enhancement of sialylation on humanized IgG-like bispecific antibody by overexpression of alpha2,6-sialyltransferase derived from Chinese hamster ovary cells. Appl. Microbiol. Biotechnol. 94: 69-80.
    Pubmed CrossRef
  26. Park H, Kim IH, Kim IY, Kim KH, Kim HJ. 2000. Expression of carbamoyl phosphate synthetase I and ornithine transcarbamoylase genes in Chinese hamster ovary DHFR-cells decreases accumulation of ammonium ion in culture media. J. Biotechnol. 81: 129-140.
    CrossRef
  27. Peng RW, Fussenegger M. 2009. Molecular engineering of exocytic vesicle traffic enhances the productivity of Chinese hamster ovary cells. Biotechnol. Bioeng. 102: 1170-1181.
    Pubmed CrossRef
  28. Rouf SA, Moo-Young M, Chisti Y. 1996. Tissue-type plasminogen activator: characteristics, applications and production technology. Biotechnol. Adv. 14: 239-266.
    CrossRef
  29. Schroder, M. 2006. The unfolded protein response. Mol. Biotechnol. 34: 279-290.
    CrossRef
  30. Seth G, Charaniya S, Wlaschin KF, Hu WS. 2007. In pursuit of a super producer - alternative paths to high producing recombinant mammalian cells. Curr. Opin. Biotechnol. 18:557-564.
    Pubmed CrossRef
  31. Tey BT, Singh RP, Piredda L, Piacentini M, Al-Rubeai M. 2000. Bcl-2 mediated suppression of apoptosis in myeloma NS0 cultures. J. Biotechnol. 79: 147-159.
    CrossRef
  32. Tigges M, Fussenegger M. 2006. Xbp1-based engineering of secretory capacity enhances the productivity of Chinese hamster ovary cells. Metab. Eng. 8: 264-272.
    Pubmed CrossRef
  33. Wong NS, Yap MG, Wang DI. 2006. Enhancing recombinant glycoprotein sialylation through CMP-sialic acid transporter over expression in Chinese hamster ovary cells. Biotechnol. Bioeng. 93: 1005-1016.
    Pubmed CrossRef
  34. Wurm FM. 2004. Production of recombinant protein therapeutics in cultivated mammalian cells. Nat. Biotechnol. 22: 1393-1398.
    Pubmed CrossRef
  35. Zhu J. 2012. Mammalian cell protein expression for biopharmaceutical production. Biotechnol. Adv. 25: 1158-1170.
    Pubmed CrossRef
  36. Zustiak MP, Dorai H, Betenbaugh MJ, Sauerwald TM. 2012. Controlling apoptosis to optimize yields of proteins from mammalian cells. Methods Mol. Biol. 801: 111-123.
    Pubmed CrossRef

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Article

Research article

J. Microbiol. Biotechnol. 2013; 23(8): 1116-1122

Published online August 28, 2013 https://doi.org/10.4014/jmb.1302.02035

Copyright © The Korean Society for Microbiology and Biotechnology.

Engineering the Cellular Protein Secretory Pathway for Enhancement of Recombinant Tissue Plasminogen Activator Expression in Chinese Hamster Ovary Cells: Effects of CERT and XBP1s Genes

Azam Rahimpour 1, Behrouz Vaziri 1, Reza Moazzami 1, Leila Nematollahi 1, Farzaneh Barkhordari 1, Leila Kokabee 1, Ahmad Adeli 1 and Fereidoun Mahboudi 1*

Biotechnology Research Center, Pasteur Institute of Iran, Tehran 1316943551, Iran

Received: February 18, 2013; Accepted: April 4, 2013

Abstract

Cell line development is the most critical and also the most time-consuming step in the
production of recombinant therapeutic proteins. In this regard, a variety of vector and cell
engineering strategies have been developed for generating high-producing mammalian cells;
however, the cell line engineering approach seems to show various results on different
recombinant protein producer cells. In order to improve the secretory capacity of a
recombinant tissue plasminogen activator (t-PA)-producing Chinese hamster ovary (CHO) cell
line, we developed cell line engineering approaches based on the ceramide transfer protein
(CERT) and X-box binding protein 1 (XBP1) genes. For this purpose, CERT S132A, a mutant
form of CERT that is resistant to phosphorylation, and XBP1s were overexpressed in a
recombinant t-PA-producing CHO cell line. Overexpression of CERT S132A increased the
specific productivity of t-PA-producing CHO cells up to 35%. In contrast, the heterologous
expression of XBP1s did not affect the t-PA expression rate. Our results suggest that CERTS132A-
based secretion engineering could be an effective strategy for enhancing recombinant t-
PA production in CHO cells.

Keywords: Chinese hamster ovary cells, cell line engineering, X-box binding protein 1, ceramide transfer protein, tissue plasminogen activator

References

  1. Bard F, Malhotra V. 2006. The formation of TGN-to-plasmamembrane transport carriers. Annu. Rev. Cell Dev. Biol. 22:439-455.
    Pubmed CrossRef
  2. Becker E, Florin L, Pfizenmaier K, Kaufmann H. 2008. An XBP-1 dependent bottle-neck in production of IgG subtype antibodies in chemically defined serum-free Chinese hamster ovary (CHO) fed-batch processes. J. Biotechnol. 135: 217-223.
    Pubmed CrossRef
  3. Borth N, Mattanovich D, Kunert R, Katinger H. 2005. Effect of increased expression of protein disulfide isomerase and heavy chain binding protein on antibody secretion in a recombinant CHO cell line. Biotechnol. Prog. 21: 106-111.
    Pubmed CrossRef
  4. Butler M. 2005. Animal cell cultures: recent achievements and perspectives in the production of biopharmaceuticals. Appl. Microbiol. Biotechnol. 68: 283-291.
    Pubmed CrossRef
  5. Cacciatore JJ, Chasin LA, Leonard EF. 2010. Gene amplification and vector engineering to achieve rapid and high-level therapeutic protein production using the Dhfr-based CHO cell selection system. Biotechnol. Adv. 28: 673-681.
    Pubmed CrossRef
  6. Figueroa Jr B, Chen S, Oyler GA, Hardwick JM, Betenbaugh MJ. 2004. Aven and Bcl-xL enhance protection against apoptosis for mammalian cells exposed to various culture conditions. Biotechnol. Bioeng. 85: 589-600.
    Pubmed CrossRef
  7. Florin L, Pegel A, Becker E, Hausser A, Olayioye MA, Kaufmann H. 2009. Heterologous expression of the lipid transfer protein CERT increases therapeutic protein productivity of mammalian cells. J. Biotechnol. 141: 84-90.
    Pubmed CrossRef
  8. Fugmann T, Hausser A, Schoffler P, Schmid S, Pfizenmaier K, Olayioye MA. 2007. Regulation of secretory transport by protein kinase D-mediated phosphorylation of the ceramide transfer protein. J. Cell Biol. 178: 15-22.
    Pubmed CrossRef
  9. Fussenegger M, Schlatter S, Datwyler D, Mazur X, Bailey JE. 1998. Controlled proliferation by multigene metabolic engineering enhances the productivity of Chinese hamster ovary cells. Nat. Biotechnol. 16: 468-472.
    Pubmed CrossRef
  10. Geserick C, Bonarius HP, Kongerslev L, Hauser H, Mueller PP. 2000. Enhanced productivity during controlled proliferation of BHK cells in continuously perfused bioreactors. Biotechnol. Bioeng. 69: 266-274.
    CrossRef
  11. Hanada K, Kumagai K, Yasuda S, Miura Y, Kawano M, Fukasawa M, Nishijima M. 2003. Molecular machinery for non-vesicular trafficking of ceramide. Nature 426: 803-809.
    Pubmed CrossRef
  12. Jaluria P, Chu C, Betenbaugh M, Shiloach J. 2008. Cells by design: a mini-review of targeting cell engineering using DNA microarrays. Mol. Biotechnol. 39: 105-111.
    Pubmed CrossRef
  13. Jayapal KP, Wlaschin KF, Hu WS, Yap MGS. 2007. Recombinant protein therapeutics from CHO cells - 20 years and counting. Chem. Eng. Prog. 103: 40-47.
  14. Josse L, Smales CM, Tuite MF. 2012. Engineering the chaperone network of CHO cells for optimal recombinant protein production and authenticity. Methods Mol. Biol. 824:595-608.
    Pubmed CrossRef
  15. Khan SU, Schroder M. 2008. Engineering of chaperone systems and of the unfolded protein response. Cytotechnology 57: 207-231.
    Pubmed CrossRef
  16. Kim JY, Kim YG, Lee GM. 2012. CHO cells in biotechnology for production of recombinant proteins: current state and further potential. Appl. Microbiol. Biotechnol. 93: 917-930.
    Pubmed CrossRef
  17. Kim SH, Lee GM. 2007. Functional expression of human pyruvate carboxylase for reduced lactic acid formation of Chinese hamster ovary cells (DG44). Appl. Microbiol. Biotechnol. 76: 659-665.
    Pubmed CrossRef
  18. Kramer O, Klausing S, Noll T. 2010. Methods in mammalian cell line engineering: from random mutagenesis to sequencespecific approaches. Appl. Microbiol. Biotechnol. 88: 425-436.
    Pubmed CrossRef
  19. Ku SC, Ng DT, Yap MG, Chao SH. 2008. Effects of overexpression of X-box binding protein 1 on recombinant protein production in Chinese hamster ovary and NS0 myeloma cells. Biotechnol. Bioeng. 99: 155-164.
    Pubmed CrossRef
  20. Ku SC, Toh PC, Lee YY, Chusainow J, Yap MG, Chao SH. 2010. Regulation of XBP-1 signaling during transient and stable recombinant protein production in CHO cells. Biotechnol. Prog. 26: 517-526.
    Pubmed
  21. Lee AH, Iwakoshi NN, Glimcher LH. 2003. XBP-1 regulates a subset of endoplasmic reticulum resident chaperone genes in the unfolded protein response. Mol. Cell Biol. 23: 74487459.
    CrossRef
  22. Meents H, Enenkel B, Werner RG, Fussenegger M. 2002. p27Kip1-mediated controlled proliferation technology increases constitutive sICAM production in CHO-DUKX adapted for growth in suspension and serum-free media. Biotechnol. Bioeng. 79: 619-627.
    Pubmed CrossRef
  23. O’Callaghan PM, James DC. 2008. Systems biotechnology of mammalian cell factories. Brief. Funct. Genomic. Proteomic. 7:95-110.
    Pubmed CrossRef
  24. Ohya T, Hayashi T, Kiyama E, Nishii H, Miki H, Kobayashi K, et al. 2008. Improved production of recombinant human antithrombin III in Chinese hamster ovary cells by ATF4 overexpression. Biotechnol. Bioeng. 100: 317-324.
    Pubmed CrossRef
  25. Onitsuka M, Kim WD, Ozaki H, Kawaguchi A, Honda K, Kajiura H, et al. 2012. Enhancement of sialylation on humanized IgG-like bispecific antibody by overexpression of alpha2,6-sialyltransferase derived from Chinese hamster ovary cells. Appl. Microbiol. Biotechnol. 94: 69-80.
    Pubmed CrossRef
  26. Park H, Kim IH, Kim IY, Kim KH, Kim HJ. 2000. Expression of carbamoyl phosphate synthetase I and ornithine transcarbamoylase genes in Chinese hamster ovary DHFR-cells decreases accumulation of ammonium ion in culture media. J. Biotechnol. 81: 129-140.
    CrossRef
  27. Peng RW, Fussenegger M. 2009. Molecular engineering of exocytic vesicle traffic enhances the productivity of Chinese hamster ovary cells. Biotechnol. Bioeng. 102: 1170-1181.
    Pubmed CrossRef
  28. Rouf SA, Moo-Young M, Chisti Y. 1996. Tissue-type plasminogen activator: characteristics, applications and production technology. Biotechnol. Adv. 14: 239-266.
    CrossRef
  29. Schroder, M. 2006. The unfolded protein response. Mol. Biotechnol. 34: 279-290.
    CrossRef
  30. Seth G, Charaniya S, Wlaschin KF, Hu WS. 2007. In pursuit of a super producer - alternative paths to high producing recombinant mammalian cells. Curr. Opin. Biotechnol. 18:557-564.
    Pubmed CrossRef
  31. Tey BT, Singh RP, Piredda L, Piacentini M, Al-Rubeai M. 2000. Bcl-2 mediated suppression of apoptosis in myeloma NS0 cultures. J. Biotechnol. 79: 147-159.
    CrossRef
  32. Tigges M, Fussenegger M. 2006. Xbp1-based engineering of secretory capacity enhances the productivity of Chinese hamster ovary cells. Metab. Eng. 8: 264-272.
    Pubmed CrossRef
  33. Wong NS, Yap MG, Wang DI. 2006. Enhancing recombinant glycoprotein sialylation through CMP-sialic acid transporter over expression in Chinese hamster ovary cells. Biotechnol. Bioeng. 93: 1005-1016.
    Pubmed CrossRef
  34. Wurm FM. 2004. Production of recombinant protein therapeutics in cultivated mammalian cells. Nat. Biotechnol. 22: 1393-1398.
    Pubmed CrossRef
  35. Zhu J. 2012. Mammalian cell protein expression for biopharmaceutical production. Biotechnol. Adv. 25: 1158-1170.
    Pubmed CrossRef
  36. Zustiak MP, Dorai H, Betenbaugh MJ, Sauerwald TM. 2012. Controlling apoptosis to optimize yields of proteins from mammalian cells. Methods Mol. Biol. 801: 111-123.
    Pubmed CrossRef