메뉴 건너뛰기




Volumn 13, Issue 5-6, 2009, Pages 556-561

Non-genetic cell-to-cell variability and the consequences for pharmacology

Author keywords

[No Author keywords available]

Indexed keywords

CELL INTERACTION; GENE EXPRESSION; GENETIC HETEROGENEITY; GENETIC VARIABILITY; HUMAN; PHENOTYPE; PROBABILITY; PROTEIN EXPRESSION; PROTEOMICS; REVIEW; TREATMENT RESPONSE;

EID: 70549093092     PISSN: 13675931     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.cbpa.2009.09.015     Document Type: Review
Times cited : (191)

References (52)
  • 2
    • 50149090966 scopus 로고    scopus 로고
    • Variability and robustness in T cell activation from regulated heterogeneity in protein levels
    • This study linked variability in the activation of a clonal population of T cells to endogenous variability in the levels of two proteins, CD8 and SHP-1. The authors measured covariation in the levels of these two proteins and using modeling, showed that this covariation reduced the diversity of T cell response.
    • Feinerman O., Veiga J., Dorfman J.R., Germain R.N., and Altan-Bonnet G. Variability and robustness in T cell activation from regulated heterogeneity in protein levels. Science 321 (2008) 1081-1084. This study linked variability in the activation of a clonal population of T cells to endogenous variability in the levels of two proteins, CD8 and SHP-1. The authors measured covariation in the levels of these two proteins and using modeling, showed that this covariation reduced the diversity of T cell response.
    • (2008) Science , vol.321 , pp. 1081-1084
    • Feinerman, O.1    Veiga, J.2    Dorfman, J.R.3    Germain, R.N.4    Altan-Bonnet, G.5
  • 3
    • 48449098623 scopus 로고    scopus 로고
    • Cancer cells display profound intra- and interline variation following prolonged exposure to antimitotic drugs
    • This paper characterized the response of 15 cell lines to 3 different classes of antimitotic drugs and found significant interline as well as intraline variation, with cells within any given cell line exhibiting multiple distinct phenotypes in response to treatment.
    • Gascoigne K.E., and Taylor S.S. Cancer cells display profound intra- and interline variation following prolonged exposure to antimitotic drugs. Cancer Cell 14 (2008) 111-122. This paper characterized the response of 15 cell lines to 3 different classes of antimitotic drugs and found significant interline as well as intraline variation, with cells within any given cell line exhibiting multiple distinct phenotypes in response to treatment.
    • (2008) Cancer Cell , vol.14 , pp. 111-122
    • Gascoigne, K.E.1    Taylor, S.S.2
  • 4
    • 56249107716 scopus 로고    scopus 로고
    • Quantitative live imaging of cancer and normal cells treated with Kinesin-5 inhibitors indicates significant differences in phenotypic responses and cell fate
    • Orth J.D., Tang Y., Shi J., Loy C.T., Amendt C., Wilm C., Zenke F.T., and Mitchison T.J. Quantitative live imaging of cancer and normal cells treated with Kinesin-5 inhibitors indicates significant differences in phenotypic responses and cell fate. Mol Cancer Ther 7 (2008) 3480-3489
    • (2008) Mol Cancer Ther , vol.7 , pp. 3480-3489
    • Orth, J.D.1    Tang, Y.2    Shi, J.3    Loy, C.T.4    Amendt, C.5    Wilm, C.6    Zenke, F.T.7    Mitchison, T.J.8
  • 5
    • 66249136447 scopus 로고    scopus 로고
    • Non-genetic origins of cell-to-cell variability in TRAIL-induced apoptosis
    • This paper examined why, in a clonal population, some cells die after a death-inducing stimulus, while others survive indefinitely. Using time-lapse imaging, flow cytometry, and mathematical modeling, the authors showed that stochastic differences in the levels of proteins are the primary causes of cell-to-cell variability in the timing and probability of death.
    • Spencer S.L., Gaudet S., Albeck J.G., Burke J.M., and Sorger P.K. Non-genetic origins of cell-to-cell variability in TRAIL-induced apoptosis. Nature 459 (2009) 428-432. This paper examined why, in a clonal population, some cells die after a death-inducing stimulus, while others survive indefinitely. Using time-lapse imaging, flow cytometry, and mathematical modeling, the authors showed that stochastic differences in the levels of proteins are the primary causes of cell-to-cell variability in the timing and probability of death.
    • (2009) Nature , vol.459 , pp. 428-432
    • Spencer, S.L.1    Gaudet, S.2    Albeck, J.G.3    Burke, J.M.4    Sorger, P.K.5
  • 7
    • 57349097152 scopus 로고    scopus 로고
    • Dynamic proteomics of individual cancer cells in response to a drug
    • This paper used time-lapse imaging of a library of proteins tagged with yellow fluorescent protein at their endogenous locus to monitor drug responses at a single-cell level. The authors identified two proteins whose levels rise in cells that survive treatment with the cancer drug camptothecin and decrease in cells that died, thereby correlating variability arising subsequent to drug treatment with cell fate.
    • Cohen A.A., Geva-Zatorsky N., Eden E., Frenkel-Morgenstern M., Issaeva I., Sigal A., Milo R., Cohen-Saidon C., Liron Y., Kam Z., et al. Dynamic proteomics of individual cancer cells in response to a drug. Science 322 (2008) 1511-1516. This paper used time-lapse imaging of a library of proteins tagged with yellow fluorescent protein at their endogenous locus to monitor drug responses at a single-cell level. The authors identified two proteins whose levels rise in cells that survive treatment with the cancer drug camptothecin and decrease in cells that died, thereby correlating variability arising subsequent to drug treatment with cell fate.
    • (2008) Science , vol.322 , pp. 1511-1516
    • Cohen, A.A.1    Geva-Zatorsky, N.2    Eden, E.3    Frenkel-Morgenstern, M.4    Issaeva, I.5    Sigal, A.6    Milo, R.7    Cohen-Saidon, C.8    Liron, Y.9    Kam, Z.10
  • 8
    • 33745451921 scopus 로고    scopus 로고
    • Oscillations and variability in the p53 system
    • 2006 0033. This study described the dynamic changes of p53 and Mdm2 expression in genetically identical cells. In response to gamma irradiation, a high degree of cell-to-cell variability was observed, with some cells showing persistent oscillations. While these oscillations were random in amplitude, the oscillating behavior of recently divided sister cells was found to be correlated.
    • Geva-Zatorsky N., Rosenfeld N., Itzkovitz S., Milo R., Sigal A., Dekel E., Yarnitzky T., Liron Y., Polak P., Lahav G., et al. Oscillations and variability in the p53 system. Mol Syst Biol 2 (2006) 2006 0033. This study described the dynamic changes of p53 and Mdm2 expression in genetically identical cells. In response to gamma irradiation, a high degree of cell-to-cell variability was observed, with some cells showing persistent oscillations. While these oscillations were random in amplitude, the oscillating behavior of recently divided sister cells was found to be correlated.
    • (2006) Mol Syst Biol , vol.2
    • Geva-Zatorsky, N.1    Rosenfeld, N.2    Itzkovitz, S.3    Milo, R.4    Sigal, A.5    Dekel, E.6    Yarnitzky, T.7    Liron, Y.8    Polak, P.9    Lahav, G.10
  • 9
    • 44349162752 scopus 로고    scopus 로고
    • Transcriptome-wide noise controls lineage choice in mammalian progenitor cells
    • Chang et al. found highly variable expression levels of the stem-cell marker Sca-1 in a clonal population of multipotent hematopoietic cells. Expression levels correlated with lineage choice and extreme outliers with very high or very low expression were able to repopulate the original protein distribution.
    • Chang H.H., Hemberg M., Barahona M., Ingber D.E., and Huang S. Transcriptome-wide noise controls lineage choice in mammalian progenitor cells. Nature 453 (2008) 544-547. Chang et al. found highly variable expression levels of the stem-cell marker Sca-1 in a clonal population of multipotent hematopoietic cells. Expression levels correlated with lineage choice and extreme outliers with very high or very low expression were able to repopulate the original protein distribution.
    • (2008) Nature , vol.453 , pp. 544-547
    • Chang, H.H.1    Hemberg, M.2    Barahona, M.3    Ingber, D.E.4    Huang, S.5
  • 10
    • 33845257870 scopus 로고    scopus 로고
    • Variability and memory of protein levels in human cells
    • This pioneering study measured fluctuations over time in the levels of 20 proteins tagged with yellow fluorescent protein at their endogenous locus in human cells. This method allowed dynamic observation of protein-level heterogeneity and examined whether cells that have higher than average protein levels eventually become lower. This mixing occurred for all proteins, and the half-life for mixing time was found to range between 0.8 and 2.5 cell generations.
    • Sigal A., Milo R., Cohen A., Geva-Zatorsky N., Klein Y., Liron Y., Rosenfeld N., Danon T., Perzov N., and Alon U. Variability and memory of protein levels in human cells. Nature 444 (2006) 643-646. This pioneering study measured fluctuations over time in the levels of 20 proteins tagged with yellow fluorescent protein at their endogenous locus in human cells. This method allowed dynamic observation of protein-level heterogeneity and examined whether cells that have higher than average protein levels eventually become lower. This mixing occurred for all proteins, and the half-life for mixing time was found to range between 0.8 and 2.5 cell generations.
    • (2006) Nature , vol.444 , pp. 643-646
    • Sigal, A.1    Milo, R.2    Cohen, A.3    Geva-Zatorsky, N.4    Klein, Y.5    Liron, Y.6    Rosenfeld, N.7    Danon, T.8    Perzov, N.9    Alon, U.10
  • 11
    • 33847208871 scopus 로고    scopus 로고
    • Timescales of genetic and epigenetic inheritance
    • Rando O.J., and Verstrepen K.J. Timescales of genetic and epigenetic inheritance. Cell 128 (2007) 655-668
    • (2007) Cell , vol.128 , pp. 655-668
    • Rando, O.J.1    Verstrepen, K.J.2
  • 13
    • 28944434119 scopus 로고    scopus 로고
    • Real-time kinetics of gene activity in individual bacteria
    • Golding I., Paulsson J., Zawilski S.M., and Cox E.C. Real-time kinetics of gene activity in individual bacteria. Cell 123 (2005) 1025-1036
    • (2005) Cell , vol.123 , pp. 1025-1036
    • Golding, I.1    Paulsson, J.2    Zawilski, S.M.3    Cox, E.C.4
  • 14
    • 0033118944 scopus 로고    scopus 로고
    • Modifying chromatin and concepts of cancer
    • Jacobson S., and Pillus L. Modifying chromatin and concepts of cancer. Curr Opin Genet Dev 9 (1999) 175-184
    • (1999) Curr Opin Genet Dev , vol.9 , pp. 175-184
    • Jacobson, S.1    Pillus, L.2
  • 15
    • 0033000990 scopus 로고    scopus 로고
    • Histone acetylases and deacetylases in cell proliferation
    • Kouzarides T. Histone acetylases and deacetylases in cell proliferation. Curr Opin Genet Dev 9 (1999) 40-48
    • (1999) Curr Opin Genet Dev , vol.9 , pp. 40-48
    • Kouzarides, T.1
  • 16
    • 25844530060 scopus 로고    scopus 로고
    • Hsp90 potentiates the rapid evolution of new traits: drug resistance in diverse fungi
    • Cowen L.E., and Lindquist S. Hsp90 potentiates the rapid evolution of new traits: drug resistance in diverse fungi. Science 309 (2005) 2185-2189
    • (2005) Science , vol.309 , pp. 2185-2189
    • Cowen, L.E.1    Lindquist, S.2
  • 17
    • 68049139696 scopus 로고    scopus 로고
    • Regulated fluctuations in nanog expression mediate cell fate decisions in embryonic stem cells
    • By monitoring the expression levels of the transcription factor Nanog, the authors found two distinguishable states in isogenic embryonic stem cells. The high Nanog state is stable while the low Nanog state is unstable and promotes differentiation. Mathematical modeling suggested that transcriptional noise underlies this behavior.
    • Kalmar T., Lim C., Hayward P., Munoz-Descalzo S., Nichols J., Garcia-Ojalvo J., and Martinez Arias A. Regulated fluctuations in nanog expression mediate cell fate decisions in embryonic stem cells. PLoS Biol 7 (2009) e1000149. By monitoring the expression levels of the transcription factor Nanog, the authors found two distinguishable states in isogenic embryonic stem cells. The high Nanog state is stable while the low Nanog state is unstable and promotes differentiation. Mathematical modeling suggested that transcriptional noise underlies this behavior.
    • (2009) PLoS Biol , vol.7
    • Kalmar, T.1    Lim, C.2    Hayward, P.3    Munoz-Descalzo, S.4    Nichols, J.5    Garcia-Ojalvo, J.6    Martinez Arias, A.7
  • 21
    • 0034517367 scopus 로고    scopus 로고
    • A single cell analysis of apoptosis. Ordering the apoptotic phenotype
    • Goldstein J.C., Kluck R.M., and Green D.R. A single cell analysis of apoptosis. Ordering the apoptotic phenotype. Ann N Y Acad Sci 926 (2000) 132-141
    • (2000) Ann N Y Acad Sci , vol.926 , pp. 132-141
    • Goldstein, J.C.1    Kluck, R.M.2    Green, D.R.3
  • 22
    • 0034280126 scopus 로고    scopus 로고
    • Rapid caspase-3 activation during apoptosis revealed using fluorescence-resonance energy transfer
    • Tyas L., Brophy V.A., Pope A., Rivett A.J., and Tavare J.M. Rapid caspase-3 activation during apoptosis revealed using fluorescence-resonance energy transfer. EMBO Rep 1 (2000) 266-270
    • (2000) EMBO Rep , vol.1 , pp. 266-270
    • Tyas, L.1    Brophy, V.A.2    Pope, A.3    Rivett, A.J.4    Tavare, J.M.5
  • 23
    • 84883829346 scopus 로고    scopus 로고
    • Modeling a snap-action, variable-delay switch controlling extrinsic cell death
    • Albeck J.G., Burke J.M., Spencer S.L., Lauffenburger D.A., and Sorger P.K. Modeling a snap-action, variable-delay switch controlling extrinsic cell death. PLoS Biol 6 (2008) 2831-2852
    • (2008) PLoS Biol , vol.6 , pp. 2831-2852
    • Albeck, J.G.1    Burke, J.M.2    Spencer, S.L.3    Lauffenburger, D.A.4    Sorger, P.K.5
  • 24
    • 33947238281 scopus 로고    scopus 로고
    • A model of immune regulation as a consequence of randomized lymphocyte division and death times
    • Hawkins E.D., Turner M.L., Dowling M.R., van Gend C., and Hodgkin P.D. A model of immune regulation as a consequence of randomized lymphocyte division and death times. Proc Natl Acad Sci U S A 104 (2007) 5032-5037
    • (2007) Proc Natl Acad Sci U S A , vol.104 , pp. 5032-5037
    • Hawkins, E.D.1    Turner, M.L.2    Dowling, M.R.3    van Gend, C.4    Hodgkin, P.D.5
  • 26
    • 52249100134 scopus 로고    scopus 로고
    • Co-expression of cytokeratin 8 and breast cancer resistant protein indicates a multifactorial drug-resistant phenotype in human breast cancer cell line
    • Liu F., Fan D., Qi J., Zhu H., Zhou Y., Yang C., Zhu Z., and Xiong D. Co-expression of cytokeratin 8 and breast cancer resistant protein indicates a multifactorial drug-resistant phenotype in human breast cancer cell line. Life Sci 83 (2008) 496-501
    • (2008) Life Sci , vol.83 , pp. 496-501
    • Liu, F.1    Fan, D.2    Qi, J.3    Zhu, H.4    Zhou, Y.5    Yang, C.6    Zhu, Z.7    Xiong, D.8
  • 27
    • 2142829549 scopus 로고    scopus 로고
    • Induction of a multifactorial resistance phenotype by high paclitaxel selective pressure in a human ovarian carcinoma cell line
    • Violini S., D'Ascenzo S., Bagnoli M., Millimaggi D., Miotti S., Canevari S., Pavan A., and Dolo V. Induction of a multifactorial resistance phenotype by high paclitaxel selective pressure in a human ovarian carcinoma cell line. J Exp Clin Cancer Res 23 (2004) 83-91
    • (2004) J Exp Clin Cancer Res , vol.23 , pp. 83-91
    • Violini, S.1    D'Ascenzo, S.2    Bagnoli, M.3    Millimaggi, D.4    Miotti, S.5    Canevari, S.6    Pavan, A.7    Dolo, V.8
  • 28
    • 0034704906 scopus 로고    scopus 로고
    • G-protein-coupled receptors function as oligomers in vivo
    • Overton M.C., and Blumer K.J. G-protein-coupled receptors function as oligomers in vivo. Curr Biol 10 (2000) 341-344
    • (2000) Curr Biol , vol.10 , pp. 341-344
    • Overton, M.C.1    Blumer, K.J.2
  • 29
    • 6344258806 scopus 로고    scopus 로고
    • Critical conformational changes in the Arp2/3 complex are induced by nucleotide and nucleation promoting factor
    • Goley E.D., Rodenbusch S.E., Martin A.C., and Welch M.D. Critical conformational changes in the Arp2/3 complex are induced by nucleotide and nucleation promoting factor. Mol Cell 16 (2004) 269-279
    • (2004) Mol Cell , vol.16 , pp. 269-279
    • Goley, E.D.1    Rodenbusch, S.E.2    Martin, A.C.3    Welch, M.D.4
  • 34
    • 38349043669 scopus 로고    scopus 로고
    • High-content single-cell drug screening with phosphospecific flow cytometry
    • Krutzik P.O., Crane J.M., Clutter M.R., and Nolan G.P. High-content single-cell drug screening with phosphospecific flow cytometry. Nat Chem Biol 4 (2008) 132-142
    • (2008) Nat Chem Biol , vol.4 , pp. 132-142
    • Krutzik, P.O.1    Crane, J.M.2    Clutter, M.R.3    Nolan, G.P.4
  • 36
    • 34250216344 scopus 로고    scopus 로고
    • Image-based multivariate profiling of drug responses from single cells
    • Loo L.H., Wu L.F., and Altschuler S.J. Image-based multivariate profiling of drug responses from single cells. Nat Methods 4 (2007) 445-453
    • (2007) Nat Methods , vol.4 , pp. 445-453
    • Loo, L.H.1    Wu, L.F.2    Altschuler, S.J.3
  • 38
    • 17644427718 scopus 로고    scopus 로고
    • Causal protein-signaling networks derived from multiparameter single-cell data
    • Sachs K., Perez O., Pe'er D., Lauffenburger D.A., and Nolan G.P. Causal protein-signaling networks derived from multiparameter single-cell data. Science 308 (2005) 523-529
    • (2005) Science , vol.308 , pp. 523-529
    • Sachs, K.1    Perez, O.2    Pe'er, D.3    Lauffenburger, D.A.4    Nolan, G.P.5
  • 39
  • 40
    • 33750205820 scopus 로고    scopus 로고
    • Profiling signaling peptides in single mammalian cells using mass spectrometry
    • Rubakhin S.S., Churchill J.D., Greenough W.T., and Sweedler J.V. Profiling signaling peptides in single mammalian cells using mass spectrometry. Anal Chem 78 (2006) 7267-7272
    • (2006) Anal Chem , vol.78 , pp. 7267-7272
    • Rubakhin, S.S.1    Churchill, J.D.2    Greenough, W.T.3    Sweedler, J.V.4
  • 41
    • 0015407423 scopus 로고
    • In vivo determination of the fractional kill of human tumor cells by chemotherapeutic agents
    • Berenbaum M.C. In vivo determination of the fractional kill of human tumor cells by chemotherapeutic agents. Cancer Chemother Rep 56 (1972) 563-571
    • (1972) Cancer Chemother Rep , vol.56 , pp. 563-571
    • Berenbaum, M.C.1
  • 45
    • 67349284051 scopus 로고    scopus 로고
    • Non-genetic heterogeneity - a mutation-independent driving force for the somatic evolution of tumours
    • Brock A., Chang H., and Huang S. Non-genetic heterogeneity - a mutation-independent driving force for the somatic evolution of tumours. Nat Rev Genet (2009)
    • (2009) Nat Rev Genet
    • Brock, A.1    Chang, H.2    Huang, S.3
  • 46
  • 48
    • 33748994704 scopus 로고    scopus 로고
    • Stochastic mRNA synthesis in mammalian cells
    • Raj et al. used a modified fluorescence in situ hybridization method to visualize individual mRNA molecules in mammalian cells. They observed extensive stochastic variation in mRNA levels in isogenic cells, owing to random switching between active and inactive states of the reporter gene.
    • Raj A., Peskin C.S., Tranchina D., Vargas D.Y., and Tyagi S. Stochastic mRNA synthesis in mammalian cells. PLoS Biol 4 (2006) e309. Raj et al. used a modified fluorescence in situ hybridization method to visualize individual mRNA molecules in mammalian cells. They observed extensive stochastic variation in mRNA levels in isogenic cells, owing to random switching between active and inactive states of the reporter gene.
    • (2006) PLoS Biol , vol.4
    • Raj, A.1    Peskin, C.S.2    Tranchina, D.3    Vargas, D.Y.4    Tyagi, S.5
  • 49
    • 15544388848 scopus 로고    scopus 로고
    • Noise propagation in gene networks
    • Pedraza J.M., and van Oudenaarden A. Noise propagation in gene networks. Science 307 (2005) 1965-1969
    • (2005) Science , vol.307 , pp. 1965-1969
    • Pedraza, J.M.1    van Oudenaarden, A.2
  • 51
    • 33645293152 scopus 로고    scopus 로고
    • An excitable gene regulatory circuit induces transient cellular differentiation
    • Suel G.M., Garcia-Ojalvo J., Liberman L.M., and Elowitz M.B. An excitable gene regulatory circuit induces transient cellular differentiation. Nature 440 (2006) 545-550
    • (2006) Nature , vol.440 , pp. 545-550
    • Suel, G.M.1    Garcia-Ojalvo, J.2    Liberman, L.M.3    Elowitz, M.B.4
  • 52
    • 33645429016 scopus 로고
    • Exact stochastic simulation of coupled chemical reactions
    • Gillespie D.T. Exact stochastic simulation of coupled chemical reactions. J Phys Chem 81 (1977) 2340-2361
    • (1977) J Phys Chem , vol.81 , pp. 2340-2361
    • Gillespie, D.T.1


* 이 정보는 Elsevier사의 SCOPUS DB에서 KISTI가 분석하여 추출한 것입니다.