Skip to main content
SpringerLink
Log in

Cellular engineering for the high-level production of recombinant proteins in mammalian cell systems

  • Invited Review Paper
  • Published:
Korean Journal of Chemical Engineering Aims and scope Submit manuscript

Abstract

The market for protein-drugs has steadily increased due their increased use as alternatives to traditional small molecule drugs. While some therapeutic proteins have been produced in microbial systems, mammalian cell systems such as Chinese hamster ovary (CHO) cells are widely used as the host cell system. To increase the efficiency of producing therapeutic proteins, many researchers have attempted to solve the critical problems that occur in mammalian cell systems. As a result, several serum-free media and advanced culture methods have been developed, and protein productivity has increased considerably through the development of efficient selection methods. However, the prevalence of apoptosis during mammalian cell culture still remains a significant problem. Based on the understanding of apoptotic mechanisms and related proteins, anti-apoptotic engineering has steadily progressed. In this study, we review the strategies that have been developed for high-level production of recombinant proteins in the CHO cell system via a selection of clones, target-gene amplification, optimization of culture systems and an inhibition of apoptosis through genetic modification.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. G. Walsh, Nat. Biotechnol., 21, 865 (2003).

    Article  CAS  Google Scholar 

  2. F.M. Wurm, Nat. Biotechnol., 22, 1393 (2004).

    Article  CAS  Google Scholar 

  3. D. K. Robinson and K.W. Memmert, Biotechnol. Bioeng., 38, 972 (1991).

    Article  CAS  Google Scholar 

  4. T.H.J. Kwaks and A. P. Otte, Trends Biotechnol., 24, 137 (2006).

    Article  CAS  Google Scholar 

  5. T. J. Wilson and I. Kola, Methods Mol. Biol., 158, 83 (2001).

    CAS  Google Scholar 

  6. G. Urlaub and L. A. Chasin, Proc. Natl. Acad. Sci. USA, 77, 4216 (1980).

    Article  CAS  Google Scholar 

  7. G. Urlaub, E. Kas, A. M. Carothers and L. A. Chasin, Cell, 33, 405 (1983).

    Article  CAS  Google Scholar 

  8. M.G. Pallavicini, P. S. DeTeresa, C. Rosette, J.W. Gray and F.M. Wurm, Mol. Cell. Biol., 10, 401 (1990).

    CAS  Google Scholar 

  9. C. Gandor, C. Leist, A. Fiechter and F.A.M. Asselbergs, FEBS Lett., 377, 290 (1995).

    Article  CAS  Google Scholar 

  10. M. Wirth, J. Bode, G. Zettlmeissl and H. Hauser, Gene, 73, 419 (1988).

    Article  CAS  Google Scholar 

  11. S.M. Browne and M. Al-Rubeai, Trends Biotechnol., 25, 425 (2007).

    Article  CAS  Google Scholar 

  12. M. S. Sinacore, D. Drapeau and S. R. Adamson, Mol. Biotechnol., 15, 249 (2000).

    Article  CAS  Google Scholar 

  13. M. J. De Jesus, P. Girard, M. Bourgeois, G. Baumgartner, B. Jacko, H. Amstutz and F.M. Wurm, Biochem. Eng. J., 17, 217 (2004).

    Article  Google Scholar 

  14. N. I. Walker, B. V. Harmon, G. C. Gobe and J. F. Kerr, Methods Achiev. Exp. Pathol., 13, 18 (1988).

    CAS  Google Scholar 

  15. A.H. Wyllie, R.G. Morris, A. L. Smith and D. Dunlop, J. Pathol., 142, 66 (1984).

    Article  Google Scholar 

  16. S.A. Susin, N. Zamzami and G. Kroemer, Biochim. Biophys. Acta, 1366, 151 (1998).

    Article  CAS  Google Scholar 

  17. X. Liu, C.N. Kim, J. Yang, R. Jemmerson and X. Wang, Cell, 86, 147 (1996).

    Article  CAS  Google Scholar 

  18. A. Ashkenazi, Nat. Rev. Cancer, 2, 420 (2002).

    Article  CAS  Google Scholar 

  19. S. Oyadomari, E. Araki and M. Mori, Apoptosis, 7, 335 (2002).

    Article  CAS  Google Scholar 

  20. J.M. Adam and S. Cory, Curr. Opin. Cell Biol., 14, 715 (2002).

    Article  Google Scholar 

  21. T. Subramanian and G. Chinnadurai, J. Cell. Biochem., 89, 1102 (2003).

    Article  CAS  Google Scholar 

  22. E.H.Y. Cheng, B. Levine, L.H. Boise, C.B. Thomson and J.M. Hardwick, Nature, 379, 554 (1996).

    Article  CAS  Google Scholar 

  23. A. J. Mastrangelo and M. J. Betenbaugh, Trends Biotechnol., 16, 88 (1998).

    Article  CAS  Google Scholar 

  24. N. Arden and M. J. Betenbaugh, Trends Biotechnol., 22, 174 (2004).

    Article  CAS  Google Scholar 

  25. A. Sanfeliu and G. Stephanopoulos, Biotechnol. Bioeng., 64, 46 (1999).

    Article  CAS  Google Scholar 

  26. J.A. Zanghi, W.A. Renner, J. E. Bailey and M. Fussenegger, Biotechnol. Prog., 16, 319 (2000).

    Article  CAS  Google Scholar 

  27. R.R. Balcarcel and G. Stephanopoulos, Biotechnol. Bioeng., 76, 1 (2001).

    Article  CAS  Google Scholar 

  28. A. Tinto, C. Gabernet, J. Vives, E. Prats, J. J. Cairo, L. Cornudella and F. Godia, J. Biotechnol., 95, 205 (2002).

    Article  CAS  Google Scholar 

  29. T.M. Sauerwald, G.A. Oyler and M. J. Betenbaugh, Biotechnol. Bioeng., 81, 329 (2003).

    Article  CAS  Google Scholar 

  30. S. L. McKenna and T.G. Cotter, Biotechnol. Bioeng., 67, 165 (2000).

    Article  CAS  Google Scholar 

  31. J. Vives, S. Juanola, J. J. Cairo and F. Godia, Metab. Eng., 5, 124 (2003).

    Article  CAS  Google Scholar 

  32. J. Vives, S. Juanola, J. J. Cairo, E. Prats, L. Cornudella and F. Godia, Biotechnol. Prog., 19, 84 (2003).

    Article  CAS  Google Scholar 

  33. A. J. Mastrangelo, J. M. Hardwick, F. Bex and M. J. Betenbaugh, Biotechnol. Bioeng., 67, 544 (2000).

    Article  CAS  Google Scholar 

  34. Y. H. Sung and G.M. Lee, Biotechnol. Prog., 21, 50 (2005).

    Article  CAS  Google Scholar 

  35. B. Figueroa, T.M. Sauerwald, G.A. Oyler, J.M. Hardwick and M. J. Betenbaugh, Metab. Eng., 5, 230 (2003).

    Article  CAS  Google Scholar 

  36. E.B. Lasunskaia, I. I. Fridlianskaia, Z. A. Darieva, M. S.R. da Silva, M. M. Kanashiro and B.A. Margulis, Biotechnol. Bioeng., 81, 496 (2003).

    Article  CAS  Google Scholar 

  37. S. O. Hwang and G.M. Lee, J. Biotechnol., 139, 89 (2009).

    Article  CAS  Google Scholar 

  38. N. S. Kim and G.M. Lee, Biotechnol. Bioeng., 78, 217 (2002).

    Article  CAS  Google Scholar 

  39. Y.H. Sung, J. S. Lee, S. H. Park, J. Koo and G. M. Lee, Metab. Eng., 9, 452 (2007).

    Article  CAS  Google Scholar 

  40. W. J. Rhee, E. J. Kim and T.H. Park, Biotechnol. Prog., 15, 1028 (1999).

    Article  CAS  Google Scholar 

  41. W. J. Rhee and T. H. Park, Biochem. Biophys. Res. Commun., 271, 186 (2000).

    Article  CAS  Google Scholar 

  42. W. J. Rhee, E. J. Kim and T. H. Park, Biochem. Biophys. Res. Commun., 295, 779 (2002).

    Article  CAS  Google Scholar 

  43. S. S. Choi, W. J. Rhee and T.H. Park, Biotechnol. Prog., 18, 874 (2002).

    Article  CAS  Google Scholar 

  44. E. J. Kim, W. J. Rhee and T. H. Park, Biochem. Biophys. Res. Commun., 285, 224 (2001).

    Article  CAS  Google Scholar 

  45. E. J. Kim, H. J. Park and T. H. Park, Biochem. Biophys. Res. Commun., 308, 523 (2003).

    Article  CAS  Google Scholar 

  46. H. J. Park, E. J. Kim, T. Y. Koo and T. H. Park, Enzyme Microb. Technol., 33, 466 (2003).

    Article  CAS  Google Scholar 

  47. E. J. Kim, W. J. Rhee and T. H. Park, Biotechnol. Prog., 20, 324 (2004).

    Article  CAS  Google Scholar 

  48. W. J. Rhee, E.H. Lee and T.H. Park, Biotechnol. Bioprocess Eng., 14, 645 (2009).

    Article  CAS  Google Scholar 

  49. E. J. Kim and T. H. Park, Biotechnol. Bioprocess Eng., 8, 76 (2003).

    Article  CAS  Google Scholar 

  50. W. J. Rhee, E.H. Lee, J. H. Park, J. E. Lee and T.H. Park, Biotechnol. Prog., 23, 1441 (2007).

    Article  CAS  Google Scholar 

  51. S. S. Choi, W. J. Rhee and T.H. Park, Biotechnol. Bioeng., 91, 793 (2005).

    Article  CAS  Google Scholar 

  52. S. S. Choi, W. J. Rhee, E. J. Kim and T. H. Park, Biotechnol. Bioeng., 95, 459 (2006).

    Article  CAS  Google Scholar 

  53. J.G. Park, S. S. Choi and T. H. Park, Process Biochem., 42, 8 (2007).

    Article  CAS  Google Scholar 

  54. T.Y. Koo, J.H. Park, H. H. Park and T.H. Park, Process Biochem., 44, 146 (2009).

    Article  CAS  Google Scholar 

  55. Z. Wang, J. H. Park, H. H. Park, W. Tan and T. H. Park, Process Biochem., in press, doi:10.1016/j.procbio.2010.03.029 (2010).

Download references

Author information

Authors and Affiliations

  1. School of Chemical and Biological Engineering, Seoul National University, Seoul, 151-744, Korea

    Ju Hyun Park, Hee Ho Park & Tai Hyun Park

Authors
  1. Ju Hyun Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hee Ho Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tai Hyun Park
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Tai Hyun Park.

Additional information

Tai Hyun Park is a Professor in the School of Chemical and Biological Engineering at Seoul National University in Korea. He received his B.S. degree (Seoul National University, Korea), M.S. degree (KAIST, Korea), and Ph.D. degree (Purdue University) all in Chemical Engineering and was a postdoctoral fellow at the University of California at Irvine. He worked for several years at the LG Biotech Research Institute and taught at Sung Kyun Kwan University before joining Seoul National University in 1997. He was a visiting professor at the University of California at Irvine and Cornell University. His research interests include cellular engineering, olfactory and taste biosensor, nanobiotechnology, biohydrogen, and biorefinery.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Park, J.H., Park, H.H. & Park, T.H. Cellular engineering for the high-level production of recombinant proteins in mammalian cell systems. Korean J. Chem. Eng. 27, 1042–1048 (2010). https://doi.org/10.1007/s11814-010-0278-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11814-010-0278-4

Key words

Search

Navigation