Torrey Pines Institute for Molecular Studies science image
Torrey Pines Institute for
Molecular Studies
3550 General Atomics Court, 2-129
San Diego, CA 92121-1122
USA
Scientists
Ruth Gjerset

Member
Head, Cancer Cell Biology Program
Tumor Suppressor / Therapy Sensitization Research Program

858.597.3880 - phone
858.597.3804 - fax
contact by email

Ruth Gjerset, Ph.D., is a member in the Division of Cell and Molecular Biology and Head of the Cancer Cell Biology Program.  She earned her Ph.D. in Biochemistry and Biophysics from the University of California, San Francisco Medical Center and received post-doctoral training at the Pasteur Institute in Paris, France, then at the University of California San Francisco and San Diego.  Prior to joining the Torrey Pines Institute for Molecular Studies in 2009, Dr. Gjerset was a faculty member of the Sidney Kimmel Cancer Center where she directed a program in cancer cell biology.

Dr. Gjerset has received the Department of Defense Gold Standard Award for breast cancer research and the Joan Scarangello Foundation Award for Lung Cancer Research.  She reviews for a number of international scientific journals in cancer research and gene therapy, and has served on grant review study sections for the National Institutes of Health National Cancer Institute, the Department of Defense Prostate Cancer Research Program and Breast Cancer Research Program, and for the Veterans Administration Merit Review.

The goals of Dr. Gjerset's program are to identify novel targets for cancer therapy and diagnosis, to develop non-toxic biological strategies for cancer treatment, and to develop strategies for improving the efficacy of conventional treatments. Her present research program focuses on the regulation and function of the p14ARF tumor suppressor, topoisomerase I, histone acetylation and DNA repair.  Her group is exploring non-toxic cell based strategies for lung and prostate cancer treatment. In addition, though a cross-disciplinary collaborative effort, her group is working to identify and validate a class of novel cancer-specific chemosensitizing drugs that could greatly improve the outcome of conventional therapies for a variety of cancers and decrease therapy toxicity.

The following projects are ongoing:

1. Combination tumor suppressor gene therapy. p53 gene therapy using a viral-mediated gene delivery approach has reached an advanced stage of clinical development. We have found that co-delivery of p14ARF is needed to optimize p53 gene therapy and we have developed combination vectors that are some 20-fold more potent than the clinical grade p53 vectors presently in use. We are presently working on improved strategies for cell-based systemic gene delivery, in order to extend this approach to the broadest array of cancers.

2. Novel targets for drug development and diagnosis. p14ARF engages in interactions and functions beyond the p53 pathway that can be exploited therapeutically and diagnostically. We and others have identified a novel nucleolar complex involving the p14ARF tumor suppressor and topoisomerase I, an important chemotherapy target. The interaction involves a region of the p14ARF protein that is not required for its p53-dependent activity and results in activation of topoisomerase I. We have shown p14ARF sensitizes tumor cells to the topoisomerase I-target drug camptothecin, independently of p53, through complex formation with topoisomerase I and that complex formation requires casein kinase-mediated topoisomerase I serine phosphorylation. Furthermore, we have found that cancer associated defects in casein kinase activity, topoisomerase I serine phosphorylation, and p14ARF/topoisomerase I complex formation correlate with certain types of therapy resistance. We are presently developing ways to target the complex to enhance p14/p53 gene therapy, as well as ways to exploit the properties of the complex for diagnostic assays for therapy resistance.



Human prostate cancer cells showing prominent subnuclear staining of p14ARF (green) in the nucleolus.
Nuclei (blue) are stained with Hoescht 33342 and cytoplasic F-actin is stained with Phalloidin (red).

Epigenetic changes at the p14ARF locus may be among the earliest occurrences in premalignancy and serve as markers for disease progression. Through a collaboration with Dr. Rebecca Fitzgerald at the University of Cambridge, U.K., Dr. Yinghui Huang is examining epigenetic changes in the p14ARF gene in Barrett's esophagus, a premalignant stage of esophageal adenocarcinoma. The identification of novel epigenetic markers could facilitate early detection and improve survival from this disease, whose incidence is increasing in western countries for unknown reasons.

3. Targeting chromatin for therapy and diagnostics. Through collaborative efforts with Vanderbilt University and the University of Toulouse, we are developing cancer-specific therapy sensitizers that target post-translational modifications of chromosomal histones. These compounds have broad application as sensitizers for for a variety of conventional therapies and may provide a general approach to reducing therapy toxicity and reversing therapy resistance in advanced cancers.

Selected Publications

  • Huang, Y., Peters, C.J., Fitzgerald, R,C,, Gjerset, R.A. (2009) Progressive silencing of p14ARF in oesophageal adenocarcinoma. J Cell Mol Med 13, 398-409.
  • Bandyopadhyay, K., Lee, C., Haghighi, A., Baneres, J. L., Parello, J., and Gjerset, R. A. (2007). Serine phosphorylation-dependent coregulation of topoisomerase I by the p14ARF tumor suppressor. Biochemistry 46, 14325-14334.
  • Huang, Y., Lee, C., Borgstrom, P., and Gjerset, R. A. (2007). Macrophage-mediated bystander effect triggered by tumor cell apoptosis. Mol Ther 15, 524-533.
  • Gjerset, R. A. (2006). DNA damage, p14ARF, nucleophosmin (NPM/B23), and cancer. J Mol Histol 37, 239-251.
  • Gjerset, R. A., and Bandyopadhyay, K. (2006). Regulation of p14ARF through subnuclear compartmentalization. Cell Cycle 5, 686-690.
  • Lee, C., Smith, B. A., Bandyopadhyay, K., and Gjerset, R. A. (2005). DNA damage disrupts the p14ARF-B23(nucleophosmin) interaction and triggers a transient subnuclear redistribution of p14ARF. Cancer Res 65, 9834-9842.
  • Huang, Y., Tyler, T., Saadatmandi, N., Lee, C., Borgstrom, P., and Gjerset, R. A. (2003). Enhanced tumor suppression by a p14ARF/p53 bicistronic adenovirus through increased p53 protein translation and stability. Cancer Res 63, 3646-3653.
  • Lebedeva, S., Bagdasarova, S., Tyler, T., Mu, X., Wilson, D. R., and Gjerset, R. A. (2001). Tumor suppression and therapy sensitization of localized and metastatic breast cancer by adenovirus p53. Hum Gene Ther 12, 763-772.
  • Haghighi, A., Lebedeva, S., and Gjerset, R. A. (1999). Preferential platination of an activated cellular promoter by cis-diamminedichloroplatinum. Biochemistry 38, 12432-12438.

Publications

  1. Bandyopadhyay, K, Banères, JL, Martin, A, Blonski, C, Parello, J, Gjerset, RA. Spermidinyl-CoA-based HAT inhibitors block DNA repair and provide cancer-specific chemo- and radiosensitization. Cell Cycle. 8(17):2779-88. Sep 1;8(17):2779-88. Epub 2009
  2. Huang Y, Peters CJ, Fitzgerald RC, Gjerset RA. Progressive silencing of p14ARF in oesophageal adenocarcinoma. J Cell Mol Med. 2008 Apr 9. [Epub ahead of print]
  3. Bandyopadhyay K, Lee C, Haghighi A, Banres JL, Parello J, Gjerset RA. Serine Phosphorylation-Dependent Coregulation of Topoisomerase I by the p14ARF Tumor Suppressor. Biochemistry. 2007 46:14325-34.
  4. Huang Y, Lee C, Borgström P, Gjerset RA. (2007), Macrophage-mediated bystander effect triggered by tumor cell apoptosis. Mol Ther 15:524-33. Epub 2007 Jan 16.
  5. Gjerset, RA. "DNA damage, p14ARF, nucleophosmin (NPM/B23), and cancer" J Mol Histol. 2006 Sep;37(5-7):239-51. Epub 2006 Jul 20. Review. (listed as one of 5 most-viewed articles for that journal in the 90-day period following publication).
  6. Gjerset RA, Bandyopadhyay K. (2006) Regulation of p14ARF through Subnuclear Compartmentalization. Cell Cycle, 5:7, 686-690.
  7. Lee C, Smith BA, Bandyopadhyay K, Gjerset RA. (2005) DNA Damage disrupts the p14ARF-B23 (Nucleophosmin) interaction and triggers a transient subnuclear redistribution of p14ARF. Cancer Res, 65:9834.
  8. Huang Y, Gjerset RA. (2003) p14ARF: Role in the cellular stress response and applications to cancer. Cancer Therapy, 1:343-351.
  9. Huang Y, Tyler T, Saadatmandi N, Lee C, Borgstrm P, Gjerset RA. (2003) Enhanced tumor suppression by a p14ARF/p53 bicistronic adenovirus through increased p53 protein translation and stability. Cancer Research, 63:3646-3653.
  10. Saadatmandi, N., Wilson, D.R., Gjerset, R.A. (2002) Therapeutic Applications of a p53 Gene Therapy vector, Ad5CMV-p53. In Encyclopedia of Cancer, 2nd edition, J. Bertino, ed., Academic Press, San Diego. Pp.425-532.
  11. Gjerset, R., Haghighi, A., Lebedeva, S., Mercola, D. (2001) Gene therapy approaches to sensitization of human prostate cancer to cisplatin. In "Methods in Molecualr Biology: Genomics Protocols", M. Starkey and E. Elaswarapu, eds. The Humana Press, Inc., Totowa, N.J. (in press).
  12. Lebedeva, S., Bagdasarova, S., Tyler, T., Mu, X., Wilson, D.R., and Gjerset, R.A. (2001) Tumor suppression and therapy sensitization of localized and metastatic breast cancer by adenovirus p53. Human Gene Therapy 12:763-772.
  13. Gjerset, R.A. and Mercola, D. (2000) Sensitization of tumors to chemotherapy through gene therapy. In "Cancer Gene Therapy: Past Achievements and Future Challenges", N. Habib, editor, Plenum Publishing Corp., New York, London, Moscow. Pp. 273-291.
  14. Gjerset, R.A., Lebedeva, S., Haghighi, A., Turla, S.T., Mercola, D. (1999) Inhibition of the Jun Kinase pathway blocks DNA repair, enhances p53-mediated apoptosis and promotes gene amplification. Cell Growth and Differ. 10: 545-554.
  15. Haghighi, A., Lebedeva, S., Gjerset, R.A. (1999) Preferential platination of an activated cellular promoter by cis-diamminedichloroplatinum. Biochemistry 38: 12432-12438.
  16. Dorigo, O., Turla, S.T., Lebedeva, S. and Gjerset, R.(1998) Sensitization of rat glioblastoma to cisplatin in vivo following restoration of wild-type p53 function. J Neurosurgery 88:535-540.
  17. Fakhrai, H., Shawler, D.L., Van Beveren, C., Lin, H., Dorigo, O., Solomon, M.J., Gjerset, R.A., Smith, L., Bartholomew, R.M., Boggiano, C.A., Gold, D.P., Sobol, R.E. (1997) Construction and characterization of retroviral vectors for interleukin-2 gene therapy. J. Immunother. 20: 437-448.
  18. Potapova, O., Haghighi, A., Bost, F., Liu, C., Birrer, M.J., Gjerset, R., Mercola, D. (1997) The jun kinase/stress-activated protein kinase pathway functions to regulate DNA repair and inhibition of the pathway sensitizes tumor cells to cisplatin. J. Biol. Chem., 272:14041-14044.
  19. Gjerset, R.A. and Sobol, R.E. (1997) Treatment resistance, apoptosis and p53 tumor suppressor gene therapy. In: Encyclopidia of Cancer, J.R. Bertino, ed., Academic Press, San Diego, vol. III, pp. 1785-1791.
  20. Sobol, R.E., Fakhrai, H., Shawler, D., Dorigo, O., Gjerset, R., et al. (1996) Immuno gene therapy of colon carcinoma and central nervous system tumors. In: Gene Therapy in Cancer, M.K. Brenner, R.C. Moden, eds., Marcel Dekker, Inc., New York, NY, pp. 139-155.
  21. Sobol, R.E., Royston, I., Fakhrai, H., Shawler, D.L.., Carson, C., Dorigo, O., Gjerset, R., Gold, D.P., Koziol, J., Mercola, D., et al (1995) Injection of colon-carcinoma patients with autologous irradiated tumor cells and fibroblasts genetically modified to secrete interleukin-2 (IL-2). A phase I study. Human Gene Therapy, 6:195-204.
  22. Gjerset, R.A., Turla, S.T., Sobol, R.E., Scalise, J., Collins, H. and Hopkins, P. (1995) Use of wild-type p53 to achieve complete treatment sensitization of tumor cells expressing endogenous mutant p53. Mol. Carcinogenesis, 214:275-285.
  23. Sobol, R.E., Fakhrai, H., Shawler, D., Gjerset, R. et al. (1995) Interleukin-2 gene therapy in a patient with glioblastoma. Gene Therapy, 2, 1-4.
  24. Shawler, D.L., Dorigo, O., Gjerset, R.A., Royston, I., Sobol, R.E. and Fakhrai, H. (1995) Comparison of gene therapy with Interleukin-2 (IL-2) gene modified fibroblasts and tumor cells in the murine CT-26 model of colorectal carcinoma. J. Immunotherapy, 17, 201-208.
  25. Fakhrai, H., Shawler, D.L., Gjerset, R., Naviaux, R.K., Koziol, J., Royston, I. and Sobol, R.E. (1995) Cytokine gene therapy with Interleukin-2 transduced fibroblasts: Effects on anti-tumor immunity. Human Gene Therapy, 6, 591-601.
  26. Gjerset, R.A., Fakhrai, H., Shawler, D., et al. (1995) Characterization of a new human glioblastoma cell line that expresses mutant p53 and lacks activation of the PDGF pathway. In Vitro Cell. Dev. Biol., 31, 207-214.
  27. Yeargin, J., Cheng, J., Yu, A.L., Gjerset, R., Bogart, M. and Haas, M. (1993) P53 mutation in acute T cell lymphoblastic leukemia is of somatic origin and is stable during establishment of T cell acute lymphoblastic leukemia cell lines. J. Clinical Invest. 91, 2111-2117.
  28. Feldman, S., Gjerset, R., Gately, D., Chien, K.R. and Feramisco, J.R. (1993) Expression of SV40 large T antigen by recombinant adenoviruses activates proliferation of corneal endothelium in vivo. J. Clinical Invest. 91, 1713-1720.
  29. Gjerset, R., Arya, J., Volkman, S. and Haas, M. (1992) Association of induction of a fully tumorigenic phenotype in murine radiation-induced T-lymphoma cells with loss of differentiation antigens, gain of CD44, and alterations in p53 protein levels. Molecular Carcinogenesis 5, 190-198.
  30. Gjerset, R., Yeargin, J., Volkman, S.K., Vila, V., Arya, J. and Haas, M. (1990) IGF-1 supports proliferation of autocrine thymic lymphoma cells with a pre-T cell phenotype. J. Immunol. 145, 3497-3501.
  31. Haas, M., Yu, A. and Gjerset, R. (1990) Characteristics of the leukemic cell in childhood acute lymphoblastic T cell leukemia at diagnosis. Leukemia 4, 230-234.
  32. Gjerset, R., Yu, A. and Haas, M. (1988) Establishment of continuous cultures of T-cell acute lymphoblastic leukemia cells at diagnosis. Cancer Res. 50, 10-14.
  33. Gjerset, R.A. and Martin, D.W. (1982) Presence of a DNA demethylating activity in the nucleus of murine erythroleukemia cells. J. Biol. Chem. 257, 8381-8583.
  34. Gjerset, R.A., Gorka, C., Hasthorpe, S., Ibarrondo, F., Lawrence, J.J. and Eisen, H. (1982) Developmental and hormonal regulation of H10 in rodents. Proc. Nat. Acad. Sci. USA 79, 2333-2337.
  35. Chabanas, A., Khoury, E., Goeltz, P., Froussard, P., Gjerset, R.A., Dod, B., Eisen, H. and Lawrence, J.J. (1985) Effects of butyric acid on cell cycle regulation and induction of histone H10 in mouse cells and tissue culture. Inducibility of H10 in the late S-G2 phase of the cell cycle. J. Mol. Biol. 183, 141-151.
  36. Gjerset, R.A., Weinberg, G. and Kapp, L. (1985) DNA fork displacement rate in cultured mammalian cells with mutations in ribonucleotide reductase. Mutation Res. 142, 199-202.
  37. Eisen, H., Gjerset, R.A. and Hasthorpe, S. (1981) Distribution and regulation of histone H10 in rodents. In: Cellular Controls in Differentiation. C.W. Lloyd and D.A. Reese, eds. Academic Press, pp. 215-226.
  38. Gjerset, R.A., Ibarrondo, F., Sergosi, S. and Eisen, H. (1981) Distribution of IP25 in mouse liver chromatin and its possible role in chromatin condensation. Biochem. Biophys., Res. Commun. 99, 349-357.
  39. Eisen, H., Hasthorpe, S., Gjerset, R.A., Nasi, S. and Keppel, F. (1980) In: In Vivo and In Vitro Erthropoiesis: The Friend System. G.R. Rossi, ed. Elsevier North Holland Press, Amsterdam, pp. 289-296.
  40. Levy-W., B., Gjerset, R.A. and McCarthy, B.J. (l977) Acetylation and phosphorylation of drosophila histones: Distribution of acetylation and phosphorylation of drosophila histones: Distribution of acetate and phosphate groups in fractionated chromatin. Biochem. Biophys. Acta 475, 168-175.
  41. Gjerset, R.A., Biessmann, H., Levy-W., B. and McCarthy, B.J. (l977) Relationship between chromatin structure and transcription. In: Molecular Mechanisms in the Control of Gene Expression. Academic Press, pp. 279-307.
  42. Biessmann, H., Gjerset, R.A., Levy-W., B. and McCarthy, B.J. (l977) The influence of chromatin structure upon in vitro transcription. In: The Organization of the Eucaryotic Genome. Bradbury, E.M. and Javaherian, K., eds. Academic Press, pp. 303-322.
  43. Gjerset, R.A., and McCarthy, B.J. (1977) Limited accessibility of chromatin satellite DNA to RNA polymerase from Escherichia coli. Proc. Natl. Acad. Sci. U.S.A. 74: 4337-4340.
  44. Biessmann, H., Gjerset, R.A., Levy-W., B. and McCarthy, B.J. (l976) Fidelity of chromatin transcription in vitro. Biochemistry 15, 4356-4363.
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