Skip to main content Accessibility help

We use cookies to distinguish you from other users and to provide you with a better experience on our websites. Close this message to accept cookies or find out how to manage your cookie settings.

Close cookie message
×
Hostname: page-component-745bb68f8f-kw2vx Total loading time: 0 Render date: 2025-02-05T15:44:32.748Z Has data issue: false hasContentIssue false

10 - Imaging Regulation of Endogenous Gene Expression in Living Subjects

Published online by Cambridge University Press:  07 September 2010

Sanjiv Sam Gambhir  and
Shahriar S. Yaghoubi
By
Vladimir Ponomarev
Sanjiv Sam Gambhir
Affiliation:
Stanford University School of Medicine, California
Shahriar S. Yaghoubi
Affiliation:
Stanford University School of Medicine, California
Get access

Summary

The past decade has witnessed a remarkable increase in our knowledge and understanding of the genetics and molecular biology of human diseases. Significant progress in the understanding of the molecular–genetic mechanisms of many diseases has been achieved with the advent of the modern molecular–biological assays. Analytical methods used in molecular biology have been introduced into mainstream research and clinical practice. In parallel, imaging methods are transforming into widely available diagnostic procedures for molecular imaging showing excellent spatial and temporal characteristics. However, there remains a tremendous gap between the advances made in molecular biology and their application to preclinical and clinical studies. Molecular reporter gene imaging can bridge contemporary molecular biology and imaging by noninvasive monitoring biochemical processes at cellular and subcellular levels in vivo.

The development of transgenic animal models of human diseases, which allows the molecular basis of the disease to be studied in a living organism, has provided new insight into disease development, progression, and treatment. Established methods for noninvasive imaging of reporter gene expression can be introduced into the existing reporter gene-based molecular–biological assay systems. In such assay systems, reporter gene expression is linked to an endogenous molecular genetic process of interest. These molecular genetic processes of interest include regulation of endogenous gene expression at the transcriptional (cis-reporter systems) and posttranscriptional (RNA-dependent reporter systems) levels, activation of specific signal transduction pathways, and specific transcription factors.

Type
Chapter
Information
Molecular Imaging with Reporter Genes , pp. 239 - 257
Publisher: Cambridge University Press
Print publication year: 2010

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Hanahan, D., Wagner, E. F., Palmiter, R. D. (2007). The origins of oncomice: a history of the first transgenic mice genetically engineered to develop cancer. Genes Dev 21(18): 2258–2270.Google Scholar
Frese, K. K., Tuveson, D. A. (2007). Maximizing mouse cancer models. Nat Rev Cancer 7(9): 645–658.Google Scholar
Blackwell, T. K., Walker, A. K. (2006). Transcription mechanisms. WormBook: 1–16.Google Scholar
Arnone, M. I., Dmochowski, I. J., Gache, C. (2004). Using reporter genes to study cis-regulatory elements. Methods Cell Biol 74: 621–652.Google Scholar
Albanese, C., Hulit, J., Sakamaki, T. et al. (2002). Recent advances in inducible expression in transgenic mice. Semin Cell Dev Biol 13(2): 129–141.Google Scholar
Kato, S., Sato, T., Watanabe, T. et al. (2005). Function of nuclear sex hormone receptors in gene regulation. Cancer Chemother Pharmacol 56(Suppl 1): 4–9.Google Scholar
Lemmen, J. G., Arends, R. J., Boxtel, A. L. et al. (2004). Tissue- and time-dependent estrogen receptor activation in estrogen reporter mice. J Mol Endocrinol 32(3): 689–701.Google Scholar
Ilagan, R., Zhang, L. J., Pottratz, J. et al. (2005). Imaging androgen receptor function during flutamide treatment in the LAPC9 xenograft model. Mol Cancer Ther 4(11): 1662–1669.Google Scholar
Ciana, P., Raviscioni, M., Mussi, P. et al. (2003). In vivo imaging of transcriptionally active estrogen receptors. Nat Med 9(1): 82–86.Google Scholar
Contag, C. H., Jenkins, D., Contag, P. R. et al. (2000). Use of reporter genes for optical measurements of neoplastic disease in vivo. Neoplasia 2(1–2): 41–52.Google Scholar
Contag, C. H., Bachmann, M. H. (2002). Advances in in vivo bioluminescence imaging of gene expression. Annu Rev Biomed Eng 4: 235–260.Google Scholar
Uhrbom, L., Nerio, E., Holland, E. C. (2004). Dissecting tumor maintenance requirements using bioluminescence imaging of cell proliferation in a mouse glioma model. Nat Med 10(11): 1257–1260.Google Scholar
Johnson, D. G., Ohtani, K., Nevins, J. R. (1994). Autoregulatory control of E2F1 expression in response to positive and negative regulators of cell cycle progression. Genes Dev 8(13): 1514–1525.Google Scholar
Karin, M., Lin, A. (2002). NF-kappaB at the crossroads of life and death. Nat Immunol 3(3): 221–227.Google Scholar
Cahir-McFarland, E. D., Davidson, D. M., Schauer, S. L. et al. (2000). NF-kappa B inhibition causes spontaneous apoptosis in Epstein–Barr virus-transformed lymphoblastoid cells. Proc Natl Acad Sci U S A 97(11): 6055–6060.Google Scholar
Keller, S. A., Hernandez-Hopkins, D., Vider, J. et al. (2006). NF-kappaB is essential for the progression of KSHV- and EBV-infected lymphomas in vivo. Blood 107(8): 3295–3302.Google Scholar
Fakhoury, J., Nimmo, G. A., Autexier, C. (2007). Harnessing telomerase in cancer therapeutics. Anticancer Agents Med Chem 7(4): 475–483.Google Scholar
Padmanabhan, P., Otero, J., Ray, P. et al. (2006). Visualization of telomerase reverse transcriptase (hTERT) promoter activity using a trimodality fusion reporter construct. J Nucl Med 47(2): 270–277.Google Scholar
Siegel, P. M., Massague, J. (2003). Cytostatic and apoptotic actions of TGF-beta in homeostasis and cancer. Nat Rev Cancer 3(11): 807–821.Google Scholar
Siegel, P. M., Shu, W., Cardiff, R. D. et al. (2003). Transforming growth factor beta signaling impairs Neu-induced mammary tumorigenesis while promoting pulmonary metastasis. Proc Natl Acad Sci U S A 100(14): 8430–8435.Google Scholar
Yin, J. J., Selander, K., Chirgwin, J. M. et al. (1999). TGF-beta signaling blockade inhibits PTHrP secretion by breast cancer cells and bone metastases development. J Clin Invest 103(2): 197–206.Google Scholar
Kang, Y., He, W., Tulley, S. et al. (2005). Breast cancer bone metastasis mediated by the Smad tumor suppressor pathway. Proc Natl Acad Sci U S A 102(39): 13909–13914.Google Scholar
Garattini, E., Gianni, M., Terao, M. (2007). Retinoids as differentiating agents in oncology: a network of interactions with intracellular pathways as the basis for rational therapeutic combinations. Curr Pharm Des 13(13): 1375–1400.Google Scholar
So, M. K., Kang, J. H., Chung, J. K. et al. (2004). In vivo imaging of retinoic acid receptor activity using a sodium/iodide symporter and luciferase dual imaging reporter gene. Mol Imaging 3(3): 163–171.Google Scholar
Haupt, S., Haupt, Y. (2006). Importance of p53 for cancer onset and therapy. Anticancer Drugs 17(7): 725–732.Google Scholar
Ohnishi, T. (2005). The role of the p53 molecule in cancer therapies with radiation and/or hyperthermia. J Cancer Res Ther 1(3): 147–150.Google Scholar
Soussi, T., Wiman, K. G. (2007). Shaping genetic alterations in human cancer: the p53 mutation paradigm. Cancer Cell 12(4): 303–312.Google Scholar
Doubrovin, M., Ponomarev, V., Beresten, T. et al. (2001). Imaging transcriptional regulation of p53-dependent genes with positron emission tomography in vivo. Proc Natl Acad Sci U S A 98(16): 9300–9305.Google Scholar
Merritt, J. A., Roth, J. A., Logothetis, C. J. (2001). Clinical evaluation of adenoviral-mediated p53 gene transfer: review of INGN 201 studies. Semin Oncol 28(5 Suppl. 16): 105–114.Google Scholar
Roth, J. A., Grammer, S. F., Swisher, S. G. et al. (2001). P53 gene replacement for cancer–interactions with DNA damaging agents. Acta Oncol 40(6): 739–744.Google Scholar
Che, J., Doubrovin, M., Serganova, I. et al. (2007). HSP70-inducible hNIS-IRES-eGFP reporter imaging: response to heat shock. Mol Imaging 6(6): 404–416.Google Scholar
Riesterer, O., Milas, L., Ang, K. K. (2007). Use of molecular biomarkers for predicting the response to radiotherapy with or without chemotherapy. J Clin Oncol 25(26): 4075–4083.Google Scholar
Liao, D., Johnson, R. S. (2007). Hypoxia: a key regulator of angiogenesis in cancer. Cancer Metastasis Rev 26(2): 281–290.Google Scholar
Semenza, G. L. (1994). Regulation of erythropoietin production. New insights into molecular mechanisms of oxygen homeostasis. Hematol Oncol Clin North Am 8(5): 863–884.Google Scholar
Forsythe, J. A., Jiang, B. H., Iyer, N. V. et al. (1996). Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Mol Cell Biol 16(9): 4604–4613.Google Scholar
Semenza, G. L., Roth, P. H., Fang, H. M. et al. (1994). Transcriptional regulation of genes encoding glycolytic enzymes by hypoxia-inducible factor 1. J Biol Chem 269(38): 23757–23763.Google Scholar
Serganova, I., Doubrovin, M., Vider, J. et al. (2004). Molecular imaging of temporal dynamics and spatial heterogeneity of hypoxia-inducible factor-1 signal transduction activity in tumors in living mice. Cancer Res 64(17): 6101–6108.Google Scholar
Thurston, G., Gale, N. W. (2004). Vascular endothelial growth factor and other signaling pathways in developmental and pathologic angiogenesis. Int J Hematol 80(1): 7–20.Google Scholar
Ruegg, C., Mutter, N. (2007). Anti-angiogenic therapies in cancer: achievements and open questions. Bull Cancer 94(9): 753–762.Google Scholar
Waisbourd, M., Loewenstein, A., Goldstein, M. et al. (2007). Targeting vascular endothelial growth factor: a promising strategy for treating age-related macular degeneration. Drugs Aging 24(8): 643–662.Google Scholar
Yla-Herttuala, S. (2006). An update on angiogenic gene therapy: vascular endothelial growth factor and other directions. Curr Opin Mol Ther 8(4): 295–300.Google Scholar
Wang, Y., Iyer, M., Annala, A. et al. (2006). Noninvasive indirect imaging of vascular endothelial growth factor gene expression using bioluminescence imaging in living transgenic mice. Physiol Genomics 24(2): 173–180.Google Scholar
Baldwin, A. S.. (1996). The NF-kappa B and I kappa B proteins: new discoveries and insights. Annu Rev Immunol 14: 649–683.Google Scholar
Doi, T. S., Takahashi, T., Taguchi, O. et al. (1997). NF-kappa B RelA-deficient lymphocytes: normal development of T cells and B cells, impaired production of IgA and IgG1 and reduced proliferative responses. J Exp Med 185(5): 953–961.Google Scholar
Carlsen, H., Moskaug, J. O., Fromm, S.H. et al. (2002). In vivo imaging of NF-kappa B activity. J Immunol 168(3): 1441–1446.Google Scholar
Rajakariar, R., Yaqoob, M. M., Gilroy, D. W. (2006). COX-2 in inflammation and resolution. Mol Interv 6(4): 199–207.Google Scholar
Liao, Z., Mason, K. A., Milas, L. (2007). Cyclo-oxygenase-2 and its inhibition in cancer: is there a role?Drugs 67(6): 821–845.Google Scholar
Ishikawa, T. O., Jain, N. K., Taketo, M. M. et al. (2006). Imaging cyclooxygenase-2 (Cox-2) gene expression in living animals with a luciferase knock-in reporter gene. Mol Imaging Biol 8(3): 171–187.Google Scholar
Nguyen, J. T., Machado, H., Herschman, H. R. (2003). Repetitive, noninvasive imaging of cyclooxygenase-2 gene expression in living mice. Mol Imaging Biol 5(4): 248–256.Google Scholar
Rooney, C., Smith, C. A., Ng, C. Y., Loftin, S., Li, C., Krance, R. A., Brenner, M. K., Heslop, H. E. (1995). Use of gene-modified virus-specific T lymphocytes to control Epstein–Barr-virus-related lymphoproliferation. Lancet 345(8941): 9–13.Google Scholar
Rosenberg, S. A., Yang, J. C., Robbins, P. F., Wunderlich, J. R., Hwu, P., Sherry, R. M., Schwartzentruber, D. J., Topalian, S. L., Restifo, N. P., Filie, A., Chang, R., Dudley, M. E. (2003). Cell transfer therapy for cancer: lessons from sequential treatments of a patient with metastatic melanoma. J Immunother 26(5): 385–393.Google Scholar
Dubey, P., Su, H., Adonai, N., Du, S., Rosato, A., Braun, J., Gambhir, S. S., Witte, O. N. (2003). Quantitative imaging of the T cell antitumor response by positron-emission tomography. Proc Natl Acad Sci U S A 100(3): 1232–1237.Google Scholar
Koehne, G., Doubrovin, M., Doubrovina, E., Zanzonico, P., Gallardo, H. F., Ivanova, A., Balatoni, J., Teruya-Feldstein, J., Heller, G., May, C., Ponomarev, V., Ruan, S., Finn, R., Blasberg, R. G., Bornmann, W., Riviere, I., Sadelain, M., O'Reilly, R. J., Larson, S. M., Tjuvajev, J. G. (2003). Serial in vivo imaging of the targeted migration of human HSV-TK-transduced antigen-specific lymphocytes. Nat Biotechnol 21(4): 405–413.Google Scholar
Soldevila, G., Castellanos, C., Malissen, M., Berg, L. J. (2001). Analysis of the individual role of the TCRzeta chain in transgenic mice after conditional activation with chemical inducers of dimerization. Cell Immunol 214(2): 123–138.Google Scholar
Macian, F., Lopez-Rodriguez, C., Rao, A. (2001). Partners in transcription: NFAT and AP-1. Oncogene 20(19): 2476–2489.Google Scholar
Kalli, K., Huntoon, C., Bell, M., McKean, D. J. (1998). Mechanism responsible for T-cell antigen receptor- and CD28- or interleukin 1 (IL-1) receptor-initiated regulation of IL-2 gene expression by NF-kappaB. Mol Cell Biol 18(6): 3140–3148.Google Scholar
Li, W., Handschumacher, R. E. (1996). Regulation of the nuclear factor of activated T cells in stably transfected Jurkat cell clones. Biochem Biophys Res Commun 219: 96–99.Google Scholar
Ponomarev, V., Doubrovin, M., Lyddane, C. et al. (2001). Imaging TCR-dependent NFAT-mediated T-cell activation with positron emission tomography in vivo. Neoplasia 3(6): 480–488.Google Scholar
Kiani, A., Rao, A., Aramburu, J. (2000). Manipulating immune responses with immunosuppressive agents that target NFAT. Immunity 12: 359–372.Google Scholar
Radu, C. G., Shu, C. J., Nair-Gill, E. et al. (2008). Molecular imaging of lymphoid organs and immune activation by positron emission tomography with a new [18F]-labeled 2′-deoxycytidine analog. Nat Med 14(7): 783–788.Google Scholar
Kang, J. H., Lee, D. S., Paeng, J. C. et al. (2005). Development of a sodium/iodide symporter (NIS)-transgenic mouse for imaging of cardiomyocyte-specific reporter gene expression. J Nucl Med 46(3): 479–483.Google Scholar
Iyer, M., Salazar, F. B., Lewis, X. et al. (2005). Non-invasive imaging of a transgenic mouse model using a prostate-specific two-step transcriptional amplification strategy. Transgenic Res 14(1): 47–55.Google Scholar
Green, L. A., Yap, C. S., Nguyen, K. et al. (2002). Indirect monitoring of endogenous gene expression by positron emission tomography (PET) imaging of reporter gene expression in transgenic mice. Mol Imaging Biol 4(1): 71–81.Google Scholar
Chen, L., Altman, A., Mier, W. et al. (2006). 99mTc-pertechnetate uptake in hepatoma cells due to tissue-specific human sodium iodide symporter gene expression. Nucl Med Biol 33(4): 575–580.Google Scholar
Qiao, J., Doubrovin, M., Sauter, B. V. et al. (2002). Tumor-specific transcriptional targeting of suicide gene therapy. Gene Ther 9(3): 168–175.Google Scholar
Gauchez, A. S., Du Moulinet D'Hardemare, A., Lunardi, J. et al. (1999). Potential use of radiolabeled antisense oligonucleotides in oncology. Anticancer Res 19(6B): 4989–4997.Google Scholar
Chao, H., Mansfield, S. G., Bartel, R. C. et al. (2003). Phenotype correction of hemophilia A mice by spliceosome-mediated RNA trans-splicing. Nat Med 9(8): 1015–1019.Google Scholar
Liu, X., Jiang, Q., Mansfield, S. G. et al. (2002). Partial correction of endogenous DeltaF508 CFTR in human cystic fibrosis airway epithelia by spliceosome-mediated RNA trans-splicing. Nat Biotechnol 20(1): 47–52.Google Scholar
Puttaraju, M., DiPasquale, J., Baker, C. C. et al. (2001). Messenger RNA repair and restoration of protein function by spliceosome-mediated RNA trans-splicing. Mol Ther 4(2): 105–114.Google Scholar
Dallinger, G., Puttaraju, M., Mitchell, L. G. et al. (2003). Development of spliceosome-mediated RNA trans-splicing (SMaRT) for the correction of inherited skin diseases. Exp Dermatol 12(1): 37–46.Google Scholar
Bhaumik, S., Walls, Z., Puttaraju, M. et al. (2004). Molecular imaging of gene expression in living subjects by spliceosome-mediated RNA trans-splicing. Proc Natl Acad Sci U S A 101(23): 8693–8698.Google Scholar
Walls, Z. F., Puttaraju, M., Temple, G. F. et al. (2008). A generalizable strategy for imaging pre-mRNA levels in living subjects using spliceosome-mediated RNA trans-splicing. J Nucl Med 49(7): 1146–1154.Google Scholar
Hasegawa, S., Jackson, W. C., Tsien, R. Y. et al. (2003). Imaging Tetrahymena ribozyme splicing activity in single live mammalian cells. Proc Natl Acad Sci U S A 100(25): 14892–14896.Google Scholar
Beelman, C. A., Parker, R. (1995). Degradation of mRNA in eukaryotes. Cell 81(2): 179–183.Google Scholar
Chen, C. Y., Shyu, A. B. (1995). AU-rich elements: characterization and importance in mRNA degradation. Trends Biochem Sci 20(11): 465–470.Google Scholar
Ragheb, J. A., Deen, M., Schwartz, R. H. (1999). CD28-Mediated regulation of mRNA stability requires sequences within the coding region of the IL-2 mRNA. J Immunol 163(1): 120–129.Google Scholar
Shaw, G., Kamen, R. (1986). A conserved AU sequence from the 3′ untranslated region of GM-CSF mRNA mediates selective mRNA degradation. Cell 46(5): 659–667.Google Scholar
Dibbens, J. A., Miller, D. L., Damert, A. et al. (1999). Hypoxic regulation of vascular endothelial growth factor mRNA stability requires the cooperation of multiple RNA elements. Mol Biol Cell 10(4): 907–919.Google Scholar
Boado, R. J., Pardridge, W. M. (1998). Ten nucleotide cis element in the 3′-untranslated region of the GLUT1 glucose transporter mRNA increases gene expression via mRNA stabilization. Brain Res Mol Brain Res 59(1): 109–113.Google Scholar
Lee, M., Choi, D., Choi, M. J. et al. (2006). Hypoxia-inducible gene expression system using the erythropoietin enhancer and 3′-untranslated region for the VEGF gene therapy. J Control Release 115(1): 113–119.Google Scholar
McGary, E. C., Rondon, I. J., Beckman, B. S. (1997). Post-transcriptional regulation of erythropoietin mRNA stability by erythropoietin mRNA-binding protein. J Biol Chem 272(13): 8628–8634.Google Scholar
Ercikan-Abali, E. A., Banerjee, D., Waltham, M. C. et al. (1997). Dihydrofolate reductase protein inhibits its own translation by binding to dihydrofolate reductase mRNA sequences within the coding region. Biochemistry 36(40): 12317–12322.Google Scholar
Mayer-Kuckuk, P., Banerjee, D., Malhotra, S. et al. (2002). Cells exposed to antifolates show increased cellular levels of proteins fused to dihydrofolate reductase: a method to modulate gene expression. Proc Natl Acad Sci U S A 99(6): 3400–3405.Google Scholar
Southern, M. M., Brown, P. E., Hall, A. (2006). Luciferases as reporter genes. Methods Mol Biol 323: 293–305.Google Scholar
Choy, G., Choyke, P., Libutti, S. K. (2003). Current advances in molecular imaging: noninvasive in vivo bioluminescent and fluorescent optical imaging in cancer research. Mol Imaging 2(4): 303–312.Google Scholar
Li, X., Zhao, X., Fang, Y. et al. (1998). Generation of destabilized green fluorescent protein as a transcription reporter. J Biol Chem 273(52): 34970–34975.Google Scholar
Hsieh, C. H., Chen, F. D., Wang, H. E. et al. (2008). Generation of destabilized herpes simplex virus type 1 thymidine kinase as transcription reporter for PET reporter systems in molecular genetic imaging. J Nucl Med 49(1): 142–150.Google Scholar
Ponomarev, V., Doubrovin, M., Serganova, I., Vider, J., Shavrin, A., Beresten, T., Ivanova, A., Ageyeva, L., Tourkova, V., Balatoni, J., Bornmann, W., Blasberg, R., Gelovani Tjuvajev, J. G. (2004). A novel triple modality reporter gene for whole body fluorescent, bioluminescent and nuclear non-invasive imaging. Eur J Nucl Med 31(5): 740–751.Google Scholar
Ray, P. D. A., Min, J. J., Tsien, R. Y., Gambhir, S. S. (2004). Imaging tri-fusion multimodality reporter gene expression in living subjects. Cancer Res 64(4): 1323–1330.Google Scholar
Ray, P., Tsien, R., Gambhir, S. S. (2007). Construction and validation of improved triple fusion reporter gene vectors for molecular imaging of living subjects. Cancer Res 67(7): 3085–3093.Google Scholar
Cecic, I., Chan, D. A., Sutphin, P. D. et al. (2007). Oxygen sensitivity of reporter genes: implications for preclinical imaging of tumor hypoxia. Mol Imaging 6(4): 219–228.Google Scholar
Green, L., Yap, C., Nguyen, N., Barrio, J., Namavari, M., Satyamurthy, N., Phelps, M., Sandgren, E., Herschman, H., Gambhir, S. (2002). Indirect monitoring of endogenous gene expression by positron emission tomography (PET) imaging of reporter gene expression in transgenic mice. Mol Imaging & Biol 4(1): 71–81.Google Scholar

Save book to Kindle

To save this book to your Kindle, first ensure no-reply@cambridge.org is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about saving to your Kindle.

Note you can select to save to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be saved to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

Find out more about the Kindle Personal Document Service.

Available formats
×

Save book to Dropbox

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Dropbox.

Available formats
×

Save book to Google Drive

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Google Drive.

Available formats
×