, Volume 53, Issue 1–3, pp 33–46

Proliferation control strategies to improve productivity and survival during CHO based production culture

A summary of recent methods employed and the effects of proliferation control in product secreting CHO cell lines
NICB special issue


Chinese Hamster Ovary cells are the primary system for the production of recombinant proteins for therapeutic use. Protein productivity is directly proportional to viable biomass, viability and culture longevity of the producer cells and a number of approaches have been taken to optimise these parameters. Cell cycle arrest, particularly in G1 phase, typically using reduced temperature cultivation and nutritional control have been used to enhance productivity in production cultures by prolonging the production phase, but the mechanism by which these approaches work is still not fully understood. In this article, we analyse the public literature on proliferation control approaches as they apply to production cell lines with particular reference to what is known about the mechanisms behind each approach.


CHO Proliferation control Productivity Temperature Cell cycle Nutrients 


  1. Alete DE, Racher AJ, Birch JR, Stansfield SH, James DC, Smales CM (2005) Proteomic analysis of enriched microsomal fractions from GS-NS0 murine myeloma cells with varying secreted recombinant monoclonal antibody productivities. Proteomics 5:4689–4704Google Scholar
  2. Al-Fageeh MB, Marchant RJ, Carden MJ, Smales CM (2006) The cold-shock response in cultured mammalian cells: harnessing the response for the improvement of recombinant protein production. Biotechnol Bioeng 93:829–835Google Scholar
  3. Al-Rubeai M, Emery AN (1990) Mechanisms and kinetics of monoclonal antibody synthesis and secretion in synchronous and asynchronous hybridoma cell cultures. J Biotechnol 16:67–85Google Scholar
  4. Al-Rubeai M, Singh RP (1998) Apoptosis in cell culture. Curr Opin Biotechnol 9:152–156Google Scholar
  5. Al-Rubeai M, Emery AN, Chalder S, Jan D (1992) Specific monoclonal antibody productivity and the cell cycle-comparisons of batch, continuous and perfusion cultures. Cytotechnology 9:85–97Google Scholar
  6. Altamirano C, Paredes C, Cairo JJ, Godia F (2000) Improvement of CHO cell culture medium formulation: simultaneous substitution of glucose and glutamine. Biotechnol Prog 16:69–75Google Scholar
  7. Altamirano C, Illanes A, Casablancas A, Gamez X, Cairo JJ, Godia C (2001a) Analysis of CHO cells metabolic redistribution in a glutamate-based defined medium in continuous culture. Biotechnol Prog 17:1032–1041Google Scholar
  8. Altamirano C, Cairó JJ, Gòdia F (2001b) Decoupling cell growth and product formation in Chinese hamster ovary cells through metabolic control. Biotechnol Bioeng 76:351–360Google Scholar
  9. Altamirano C, Paredes C, Illanes A, Cairo JJ, Godia F (2004) Strategies for fed-batch cultivation of t-PA producing CHO cells: substitution of glucose and glutamine and rational design of culture medium. J Biotechnol 110:171–179Google Scholar
  10. Altamirano C, Illanes A, Becerra S, Cairo JJ, Godia F (2006) Considerations on the lactate consumption by CHO cells in the presence of galactose. J Biotechnol 125:547–556Google Scholar
  11. Andersen DC, Bridges T, Gawlitzek M, Hoy C (2000) Multiple cell culture factors can affect the glycosylation of Asn-184 in CHO-produced tissue-type plasminogen activator. Biotechnol Bioeng 70:25–31Google Scholar
  12. Baghdoyan S, Dubreuil P, Eberle F, Gomez S (2000) Capture of cytokine-responsive genes (NACA and RBM3) using a gene trap approach. Blood 95:3750–3757Google Scholar
  13. Baik JY, Lee MS, An SR, Yoon SK, Joo EJ, Kim YH, Park HW, Lee GM (2006) Initial transcriptome and proteome analyses of low culture temperature-induced expression in CHO cells producing erythropoietin. Biotechnol Bioeng 93:361–371Google Scholar
  14. Baldi A, Battista T, De Luca A, Santini D, Rossiello L, Baldi F, Natali PG, Lombardi D, Picardo M, Felsani A, Paggi MG (2003) Identification of genes down-regulated during melanoma progression: a cDNA array study. Exp Dermatol 12:213–218Google Scholar
  15. Bi JX, Shuttleworth J, Al-Rubeai M (2004) Uncoupling of cell growth and proliferation results in enhancement of productivity in p21CIP1-arrested CHO cells. Biotechnol Bioeng 85:741–749Google Scholar
  16. Bollati-Fogolin M, Forno G, Nimtz M, Conradt HS, Etcheverrigaray M, Kratje R (2005) Temperature reduction in cultures of hGM-CSF-expressing CHO cells: effect on productivity and product quality. Biotechnol Prog 21:17–21Google Scholar
  17. Buckbinder L, Talbott R, Velasco-Miguel S, Takenaka I, Faha B, Seizinger BR, Kley N (1995) Nduction of the growth inhibitor IGF-binding protein 3 by p53. Nature 377:646–649Google Scholar
  18. Buckley AR, Leff MA, Buckley DJ, Magnuson NS, de Jong G, Gout PW (1996) Alteration in pim-1 and c-myc expression associated with sodium butyrate-induced growth factor dependency in autonomous rat Nb2 lymphoma cells. Cell Growth Differ 7:1713–1721Google Scholar
  19. Carvalhal AV, Marcelino I, Carrondo MJT (2003) Metabolic changes during cell growth inhibition by p27 overexpression. Appl Microbiol Biotechnol 63:164–173Google Scholar
  20. Chang KH, Kim KS, Kim JH (1999) N-Acetylcysteine increases the biosynthesis of recombinant EPO in apoptotic Chinese hamster ovary cells. Free Rad Res 30:85–91Google Scholar
  21. Chappell SA, Mauro VP (2003) The internal ribosome entry site (IRES) contained within the RNA-binding motif protein 3 (Rbm3) mRNA is composed of functionally distinct elements. J Biol Chem 278:33793–33800Google Scholar
  22. Chappell SA, Owens GC, Mauro VP (2001) A 5’ leader of Rbm3, a cold stress-induced mRNA, mediates internal initiation of translation with increased efficiency under conditions of mild hypothermia. J Biol Chem 276:36917–36922Google Scholar
  23. Cherlet M, Marc A (2000) Stimulation of monoclonal antibody production of hybridoma cells by butyrate: evaluation of a feeding strategy and characterization of cell behavior. Cytotechnology 32:17–29Google Scholar
  24. Chuppa S, Tsai YS, Yoon S, Shackleford S, Rozales C, Bhat R, Tsay G, Matanguihan C, Konstantinov K, Naveh D (1997) Fermentor temperature as a tool for control of high density perfusion cultures of mammalian cells. Biotechnol Bioeng 55:328–338Google Scholar
  25. Clark KJ, Chaplin FW, Harcum SW (2004) Temperature effects on product-quality-related enzymes in batch CHO cell cultures producing recombinant tPA. Biotechnol Prog 20:1888–1892Google Scholar
  26. Danno S, Itoh K, Matsuda T, Fujita J (2000) Decreased expression of mouse Rbm3, a cold-shock protein, in Sertoli cells of cryptorchid testis. Am J Pathol 156:1685–1692Google Scholar
  27. Davis R, Schooley K, Rasmussen B, Thomas J, Reddy P (2000) Effect of PDI overexpression on recombinant protein secretion in CHO cells. Biotechnol Prog 16:736–743Google Scholar
  28. Derry JM, Kerns JA, Francke U (1995) RBM3, a novel human gene Xp11.23 with putative RNA-binding domain. Hum Mol Genet 4:2307–2311Google Scholar
  29. Dresios J, Aschrafi A, Owens GC, Vanderklish PW, Edelman GM, Mauro VP (2005) Cold stress-induced protein Rbm3 binds 60S ribosomal subunits, alters microRNA levels, and enhances global protein synthesis. Proc Natl Acad Sci USA 102:1865–1870Google Scholar
  30. El-Deiry W, Tokino T, Velculescu V, Levy D, Parsons R, Trent J, Lin D, Mercer W, Kinzler K, Vogelstein B (1993) WAF1, a potential mediator of p53 tumor suppression. Cell 75:817–825Google Scholar
  31. El-Deiry WS, Harper JW, O’Connor PM, Velculescu VE, Canman CE, Jackman J, Pietenpol JA, Burrell M, Hill DE, Wang Y, Wiman KG, Mercer WE, Kastan MB, Kohn KW, Elledge SJ, Kinzler KW, Vogelstein B (1994) WAF1/CIP1 is induced in p53-mediated G1 arrest and apoptosis. Cancer Res 54:1169–1174Google Scholar
  32. Fiore M, Degrassi F (1999) Dimethyl sulfoxide restores contact inhibition-induced growth arrest and inhibits cell density-dependent apoptosis in hamster cells. Exp Cell Res 251:102–110Google Scholar
  33. Fiore M, Zanier R, Degrassi F (2002) Reversible G1 arrest by dimethyl sulfoxide as a new method to synchronize Chinese hamster cells. Mutagenesis 17:419–424Google Scholar
  34. Fogolin MB, Wagner R, Etcheverrigaray M, Kratje R (2004) Impact of temperature reduction and expression of yeast pyruvate carboxylase on hGM-CSF-producing CHO cells. J Biotechnol 109:179–191Google Scholar
  35. Fox SR, Patel UA, Yap MG, Wang DI (2004) Maximizing interferon-gamma production by Chinese hamster ovary cells through temperature shift optimization: experimental and modeling. Biotechnol Bioeng 85:177–184Google Scholar
  36. Fox SR, Tan HK, Tan MC, Wong SC, Yap MG, Wang DI (2005) A detailed understanding of the enhanced hypothermic productivity of interferon-gamma by Chinese-hamster ovary cells. Biotechnol Appl Biochem 41:255–264Google Scholar
  37. Fujita J (1999) Cold shock response in mammalian cells. J Mol Microbiol Biotechnol 1:243–255Google Scholar
  38. Furukawa K, Ohsuye K (1998) Effect of culture temperature on a recombinant CHO cell line producing a C-terminal α-amidating enzyme. Cytotechnology 26:153–164Google Scholar
  39. Furukawa K, Ohsuye K (1999) Enhancement of productivity of recombinant α-amidating enzyme by low temperature culture. Cytotechnology 31:85–94Google Scholar
  40. Fussenegger M, Mazur X, Bailey JE (1997) A novel cytostatic process enhances the productivity of Chinese hamster ovary cells. Biotechnol Bioeng 55:927–939Google Scholar
  41. 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 16:468–472Google Scholar
  42. Fussenegger M, Fassnacht D, Schwartz R, Zanghi JA, Graf M, Bailey JE, Portner R (2000) Regulated overexpression of the survival factor bcl-2 in CHO cells increases viable cell density in batch culture and decreases DNA release in extended fixed-bed cultivation. Cytotechnology 32:45–61Google Scholar
  43. Garcia-Bermejo L, Vilaboa NE, Perez C, Galan A, DeBlas E, Aller P (1997) Modulation of heat-shock protein 70 (HSP70) gene expression by sodium butyrate in U-937 promonocytic cells: relationships with differentiation and apoptosis. Exp Cell Res 236:268–274Google Scholar
  44. Grana X, Reddy EP (1995) Cell cycle control in mammalian cells: role of cyclins, cyclin-dependent kinases (CDKs), growth suppressor genes and cyclin-dependent kinase inhibitors (CKIs). Oncogene 11:211–219Google Scholar
  45. Hakura A, Mochida H, Yamatsu K (1993) Dimethyl sulfoxide (DMSO) is mutagenic for bacterial mutagenicity tester strains. Mutat Res 303:127–133Google Scholar
  46. Hayduk EJ, Choe LH, Lee KH (2004) A two-dimensional electrophoresis map of Chinese hamster ovary cell proteins based on fluorescence staining. Electrophoresis 25:2545–2556Google Scholar
  47. Hayles J, Fisher D, Woollard A, Nurse P (1994) Temporal order of S phase and mitosis in fission yeast is determined by the stat of the p34cdc2 mitotic B cyclin complex. Cell 78:813–822Google Scholar
  48. Hendrick V, Winnepenninckx P, Abdelkafi CV, Andeputte O, Cherlet M, Marique T, Renemann G, Loa A, Kretzmer G, Werenne J (2001) Increased productivity of recombinant tissular plasminogen activator (t-PA) by butyrate and shift of temperature: a cell cycle phases analysis. Cytotechnology 36:71–83Google Scholar
  49. Hengst L, Dulic V, Slingerland JM, Lees E, Reed SI (1994) A cell cycle-regulated inhibitor of cyclin-dependent kinases. Proc Natl Acad Sci USA 91:5291–5295Google Scholar
  50. Holland DB, Roberts SG, Wood EJ, Cunliffe WJ (1993) Cold shock induces the synthesis of stress proteins in human keratinocytes. J Invest Dermatol 101:196–199Google Scholar
  51. Huang DC, O’Reilly LA, Strasser A, Cory S (1997) The anti-apoptosis function of Bcl-2 can be genetically separated from its inhibitory effect on cell cycle entry. EMBO J 16:4628–4638Google Scholar
  52. Hunt L, Batard P, Jordan M, Wurm FM (2002) Fluorescent proteins in animal cells for process development: optimization of sodium butyrate treatment as an example. Biotechnol Bioeng 77:528–537Google Scholar
  53. Ibarra N, Watanabe S, Bi J-X, Shuttleworth J, Al-Rubeai M (2003) Modulation of cell cycle for enhancement of antibody productivity in perfusion culture of NS0 cells. Biotech Prog 19:224–228Google Scholar
  54. Jones PG, Inouye M (1994) The cold-shock response hot topic. Mol Microbiol 11:811–818Google Scholar
  55. Jorjani P, Ozturk SS (1999) Effects of cell density and temperature on oxygen consumption rate for different mammalian cell lines. Biotechnol Bioeng 64:349–356Google Scholar
  56. Kaufmann H, Mazur X, Fussenegger M, Bailey JE (1999) Influence of low temperature on productivity, proteome and protein phosphorylation of CHO cells. Biotechnol Bioeng 63:573–582Google Scholar
  57. Kaufmann H, Mazur X, Marone R, Bailey J, Fussenegger M (2001) Comparative analysis of two controlled proliferation strategies regarding product quality, influence on tetracycline–regulated gene expression and productivity. Biotechnol Bioeng 72:592–602Google Scholar
  58. Kim NS, Lee GM (2001) Overexpression of bcl-2 inhibits sodium butyrate-induced apoptosis in Chinese hamster ovary cells resulting in enhanced humanized antibody production. Biotechnol Bioeng 71:184–193Google Scholar
  59. Kim NS, Lee GM (2002) Inhibition of sodium butyrate-induced apoptosis in recombinant Chinese hamster ovary cells by constitutively expressing antisense RNA of caspase-3. Biotechnol Bioeng 78:217–228Google Scholar
  60. Kita H, Carmichael J, Swartz J, Muro S, Wyttenbach A, Matsubara K, Rubinsztein DC, Kato K (2002) Modulation of polyglutamine-induced cell death by genes identified by expression profiling. Hum Mol Genet 11:2279–2287Google Scholar
  61. Ko LJ, Prives C (1996) p53: puzzle and paradigm. Genes Dev 10:1054–1072Google Scholar
  62. Kondo K, Kowalski LR, Inouye M (1992) Cold shock induction of yeast NSR1 protein and its role in pre-rRNA processing. J Biol Chem 267:16259–16265Google Scholar
  63. Kurano N, Leist C, Messi F, Kurano S, Fiechter A (1990) Growth behavior of chinese hamster ovary cells in a compact loop bioreactor. 2. Effects of medium components and waste products. J Biotechnol 15:113–128Google Scholar
  64. Lee SK, Lee GM (2003) Development of apoptosis-resistant dihydrofolate reductase-deficient Chinese hamster ovary cell line. Biotechnol Bioeng 82:872–876Google Scholar
  65. Li CJ, Elsasser TH (2005) Butyrate-induced apoptosis and cell cycle arrest in bovine kidney epithelial cells: involvement of caspase and proteasome pathways. J Anim Sci 83:89–97Google Scholar
  66. Liu CH, Chu IM, Hwang SM (2001) Pentanoic acid, a novel protein synthesis stimulant for chinese hamster ovary (CHO) cells. J Biosci Bioeng 91:71–75Google Scholar
  67. Lloyd DR, Holmes P, Jackson LP, Emery AN, Al-Rubeai M (2000) Relationship between cell size, cell cycle and specific recombinant protein productivity. Cytotechnology 34:59–70Google Scholar
  68. Mazur X, Fussenegger M, Renner WA, Bailey JE (1998) Higher productivity of growth-arrested Chinese hamster ovary cells expressing the cyclin-dependent kinase inhibitor p27. Biotechnol Prog 14:705–713Google Scholar
  69. Mazur X, Eppenberger HM, Bailey JE, Fussenegger M (1999) A novel autoregulated proliferation-controlled production process using recombinant CHO cells. Biotechnol Bioeng 65:144–150Google Scholar
  70. Meents H, Enenkel B, Eppenberger HM, Werner RG, Fussenegger M (2002) Impact of coexpression and coamplification of sICAM and antiapoptosis determinants bcl-2/bcl-x(L) on productivity, cell survival, and mitochondria number in CHO-DG44 grown in suspension and serum-free media. Biotechnol Bioeng 80:706–716 Google Scholar
  71. Monneret C (2005) Histone deacetylase inhibitors. Eur J Med Chem 40:1–13Google Scholar
  72. Moore A, Mercer J, Dutina G, Donahue CJ, Bauer KD, Mather JP, Etcheverry T, Ryll T (1997) Effects of temperature shift on cell cycle, apoptosis and nucleotide pools in CHO cell batch cultures. Cytotechnology 23:47–54Google Scholar
  73. Nishiyama H, Higashitsuji H, Yokoi H, Itoh K, Danno S, Matsuda T, Fujita J (1997a) Cloning and characterization of human CIRP (cold-inducible RNA-binding protein) cDNA and chromosomal assignment of the gene. Gene 204:115–120Google Scholar
  74. Nishiyama H, Itoh K, Kaneko Y, Kishishita M, Yoshida O, Fujita J (1997b) A glycine-rich RNA-binding protein mediating cold-inducible suppression of mammalian cell growth. J Cell Biol 137:899–908Google Scholar
  75. Nurse P (1994) Ordering S phase and M phase in the cell cycle. Cell 79:547–550Google Scholar
  76. O’Reilly LA, Huang DCS, Strasser A (1996) The cell death inhibitor bcl-2 and its homologues influence control of cell cycle entry. EMBO J 15:6979–6990Google Scholar
  77. Ohsaka Y, Ohgiya S, Hoshino T, Ishizaki K (2002) Phosphorylation of c-Jun N-terminal kinase in human hepatoblastoma cells is transiently increased by cold exposure and further enhanced by subsequent warm incubation of the cells. Cell Physiol Biochem 12:111–118Google Scholar
  78. Ostermeier M, De Sutter K, Georgiou G (1996) Eukaryotic protein disulfide isomerase complements Escherichia coli dsbA mutants and increases the yield of a heterologous secreted protein with disulfide bonds. J Biol Chem 271:10616–10622Google Scholar
  79. Ozturk S, Riley M, Palsson B (1992) Effects of ammonia and lactate on hybridoma growth, metabolism and antibody production. Biotechnol Bioeng 39:418–431Google Scholar
  80. Palermo DP, DeGruf ME, Marotti KR, Rehberg E, Post LE (1992) Production of analytical quantities of recombinant proteins in Chinese hamster ovary cells using sodium butyrate to elevate gene expression. J Biotechnol 19:35–48Google Scholar
  81. Phadtare S, Alsina J, Inouye M (1999) Cold-shock response and cold-shock proteins. Curr Opin Microbiol 2:175–180Google Scholar
  82. Pikaart MJ, Recillas-Targa F, Felsenfeld G (1998) Loss of transcriptional activity of a transgene is accompanied by DNA methylation and histone deacetylation and is prevented by insulators. Genes Dev 12:2852–2862Google Scholar
  83. Ponzio G, Loubat A, Rochet N, Turchi L, Rezzonico R, Far DF, Dulic V, Rossi B (1998) Early G(1) growth arrest of hybridoma B cells by DMSO involves cyclin D2 inhibition and p21([CIP1]) induction. Oncogene 17:1159–1166Google Scholar
  84. Puck TT, Cieciura SJ, Robinson A (1958) Genetics of somatic mammalian cells. J Mol Med 108:945–955Google Scholar
  85. Reitzer L, Wice B, Kennell D (1979) Evidence that glutamine, not sugar, is the major energy source for cultured hela cells. J Biol Chem 254:2669–2676Google Scholar
  86. Reynisdottir I, Polyak K, Iavarone A, Massague J (1995) Kip/Cip and Ink4 inhibitors cooperate to induce cell-cycle arrest in response to TGF-b. Genes Dev 9:1831–1845Google Scholar
  87. Robinson AS, Hines V, Wittrup KD (1994) Protein disulfide isomerase overexpression increases secretion of foreign proteins in Saccharomyces cerevisiae. Biotechnology 12:381–384Google Scholar
  88. Rowan S, Ludwig RL, Haupt Y, Bates S, Lu X, Oren M, Vousden KH (1996) Specific loss of apoptotic but not cell-cycle arrest function in a human tumor derived p53 mutant. EMBO J 15:827–838Google Scholar
  89. Ryll T, Dutina G, Reyes A, Gunson J, Krummen L, Etcheverry T (2000) Performance of small-scale CHO perfusion cultures using an acoustic cell filtration device for cell retention: characterization of separation efficiency and impact of perfusion on product quality. Biotechnol Bioeng 69:440–449Google Scholar
  90. Sawai M, Takase K, Teraoka H, Tsukada K (1990) Reversible G1 arrest in the cell cycle of human lymphoid cell lines by dimethyl sulfoxide. Exp Cell Res 187:4–10Google Scholar
  91. Schatz SM, Kerschbaumer RJ, Gerstenbauer G, Kral M, Dorner F, Scheiflinger F (2003) Higher expression of Fab antibody fragments in a CHO cell line at reduced temperature. Biotechnol Bioeng 84:433–438Google Scholar
  92. Sgambato A, Cittadini A, Faraglia B, Weinstein IB (2000) Multiple functions of p27(Kip1) and its alterations in tumor cells: a review. J Cell Physiol 183:18–27Google Scholar
  93. Sheikh MS, Carrier F, Papathanasiou MA, Hollander MC, Zhan Q, Yu K, Fornace AJ Jr (1997) Identification of several human homologs of hamster DNA damage-inducible transcripts. Cloning and characterization of a novel UV-inducible cDNA that codes for a putative RNA-binding protein. J Biol Chem 272:26720–26726Google Scholar
  94. Shusta EV, Raines RT, Pluckthun A, Wittrup KD (1998) Increasing the secretory capacity of Saccharomyces cerevisiae for production of single-chain antibody fragments. Nat Biotechnol 16:773–777Google Scholar
  95. Simpson NH, Milner AE, AlRubeai M (1997) Prevention of hybridoma cell death by bcl-2 during suboptimal culture conditions. Biotechnol Bioeng 54:1–16Google Scholar
  96. Simpson NH, Singh RP, Emery AN, Al-Rubeai M (1999) Bcl-2 overexpression reduces growth rate and prolongs G1 phase in continuous chemostat cultures of hybridoma cells. Biotechnol Bioeng 64:174–186Google Scholar
  97. Smales CM, Dinnis DM, Stansfield SH, Alete D, Sage EA, Birch JR, Racher AJ, Marshall CT, James DC (2004) Comparative proteomic analysis of GS-NS0 murine myeloma cell lines with varying recombinant monoclonal antibody production rate. Biotechnol Bioeng 88:474–488Google Scholar
  98. Sonna LA, Fujita J, Gaffin SL, Lilly CM (2002) Effects of heat and cold stress on mammalian gene expression. J Appl Physiol 92:1725–1742Google Scholar
  99. Srinivas S, Sironmani TA, Shanmugam G (1991) Dimethyl sulfoxide inhibits the expression of early growth-response genes and arrests fibroblasts at quiescence. Exp Cell Res 196:279–286Google Scholar
  100. Stein GS, Baserga R, Giordano A, Denhardt DT (1999) The molecular basis of cell cycle and growth control. Wiley-Liss, NY, p 389Google Scholar
  101. Sugimoto M, Martin N, Wilks DP, Tamai K, Huot TJ, Pantoja C, Okumura K, Serrano M, Hara E (2002) Activation of cyclin D1-kinase in murine fibroblasts lacking both p21 (Cip1) and p27 (Kip1). Oncogene 21:8067–8074Google Scholar
  102. Sun WH, Coleman TR, DePamphilis ML (2002) Cell cycle-dependent regulation of the association between origin recognition proteins and somatic cell chromatin. EMBO J 21:1437–1446Google Scholar
  103. Tey BT, Al-Rubeai M (2005) Effect of Bcl-2 overexpression on cell cycle and antibody productivity in chemostat cultures of myeloma NS0 cells. J Biosci Bioeng 100:303–310Google Scholar
  104. Toyoshima H, Hunter T (1994) p27, a novel inhibitor of G1 cyclin-Cdk protein kinase activity, is related to p21. Cell 78:67–74Google Scholar
  105. Trummer E, Fauland K, Seidinger S, Schriebl K, Lattenmayer C, Kunert R, Vorauer-Uhl K, Weik R, Borth N, Katinger H, Muller D (2006) Process parameter shifting: part II. Biphasic cultivation – a tool for enhancing the volumetric productivity of batch processes using Epo-Fc expressing CHO cells. Biotechnol Bioeng 94:1045–1052Google Scholar
  106. Wang SY, Melkoumian Z, Woodfork KA, Cather C, Davidson AG, Wonderlin WF, Strobl JS (1998) Evidence for an early G1 ionic event necessary for cell cycle progression and survival in the MCF-7 human breast carcinoma cell line. J Cell Physiol 176:456–464Google Scholar
  107. Wassmann H, Greiner C, Hulsmann S, Moskopp D, Speckmann EJ, Meyer J, Van Aken H (1998) Hypothermia as cerebroprotective measure. Experimental hypoxic exposure of brain slices and clinical application in critically reduced cerebral perfusion pressure. Neurol Res 20:S61–S65Google Scholar
  108. Watanabe S, Shuttleworth J, Al-Rubeai M (2002) Regulation of cell cycle and productivity in NS0 cells by the over-expression of p21CIP1. Biotechnol Bioeng 77:1–7Google Scholar
  109. Wellmann S, Buhrer C, Moderegger E, Zelmer A, Kirschner R, Koehne P, Fujita J, Seeger K (2004) Oxygen-regulated expression of the RNA-binding proteins RBM3 and CIRP by a HIF-1-independent mechanism. J Cell Sci 117:1785–1794Google Scholar
  110. Wong DC, Wong KT, Lee YY, Morin PN, Heng CK, Yap MG (2006) Transcriptional profiling of apoptotic pathways in batch and fed-batch CHO cell cultures. Biotechnol Bioeng 94:373–382Google Scholar
  111. Wright CF, Oswald BW, Dellis S (2001) Vaccinia virus late transcription is activated in vitro by cellular heterogeneous nuclear ribonucleoproteins. J Biol Chem 276:40680–40686Google Scholar
  112. Wurm FM (2004) Production of recombinant protein therapeutics in cultivated mammalian cells. Nat Biotechnol 22:1393–1398Google Scholar
  113. Xue S, Rao PN (1981) Sodium butyrate blocks HeLa cells preferentially in early G1 phase of the cell cycle. J Cell Sci 51:163–171Google Scholar
  114. Xue JH, Nonoguchi K, Fukumoto M, Sato T, Nishiyama H, Higashitsuji H, Itoh K, Fujita J (1999) Effects of ischemia and H2O2 on the cold stress protein CIRP expression in rat neuronal cells. Free Radic Biol Med 27:1238–1244Google Scholar
  115. Yang C, Carrier F (2001) The UV-inducible RNA-binding protein A18 (A18 hnRNP) plays a protective role in the genotoxic stress response. J Biol Chem 276:47277–47284Google Scholar
  116. Yoon SK, Kim SH, Lee GM (2003a) Effect of low culture temperature on specific productivity and transcription level of anti-4-1BB antibody in recombinant Chinese hamster ovary cells. Biotechnol Prog 19:1383–1386Google Scholar
  117. Yoon SK, Song JY, Lee GM (2003b) Effect of low culture temperature on specific productivity, transcription level, and heterogeneity of erythropoietin in Chinese hamster ovary cells. Biotechnol Bioeng 82:289–298Google Scholar
  118. Yoon SK, Hwang SO, Lee GM (2004) Enhancing effect of low culture temperature on specific antibody productivity of recombinant Chinese hamster ovary cells: clonal variation. Biotechnol Prog 20:1683–1688Google Scholar
  119. Yoon SK, Hong JK, Choo SH, Song JY, Park HW, Lee GM (2006) Adaptation of Chinese hamster ovary cells to low culture temperature: cell growth and recombinant protein production. J Biotechnol 122:463–472Google Scholar
  120. Zeng AP, Deckwer WD (1999) Model simulation and analysis of perfusion culture of mammalian cells at high cell density. Biotechnol Prog 15:373–382Google Scholar
  121. Zeng AP, Deckwer WD, Hu WS (1998) Determinants and rate laws of growth and death of hybridoma cells in continuous culture. Biotechnol Bioeng 57:642–654Google Scholar

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© Springer Science+Business Media, Inc. 2007

Authors and Affiliations

  1. 1.National Institute for Cellular Biotechnology, Dublin City UniversityDublinIreland

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