Peter C. Keng, Ph.D

Research Overview

Concentration: Mechanisms of Radiation Sensitivity in Solid Tumors

GEBS Cluster Affiliations:
  PWD - Pathways of Human Disease
  TOX - Toxicology

Our research objectives are to determine 1) the role of p53 in radiation sensitivity and cell cycle delay, 2) the mechanisms by which interferon beta enhances the radiation sensitivity of human tumor cells and 3) the biochemical and functional properties of G2/M checkpoint proteins.

The relationships between p53 and radiation sensitivity are being investigated with mouse cell lines transfected with different forms of p53 mutations. The results will determine the phenotypic and functional changes of p53 and their involvement in the radiation sensitivity of mammalian cells. The goal of the interferon study is to investigate whether its effect on radiation sensitivity is mediated through the Ku 70/80 and DNA-dependent protein kinase (DNA-PK) activity. Ku 70/80 and DNA-PK are known to be involved in the repair of radiation-induced DNA double-strand breaks. A better understanding of the interaction between interferon beta and radiation would improve the efficacy of cancer therapy with combined treatments of radiation and drugs.

We are also studying the function of a yeast G2/M checkpoint gene, rad9, in mammalian cells. Mutation of rad9 in yeast abrogates the function of G2/M arrest and makes the cells very sensitive to ionizing radiation. We have identified a rad9 equivalent gene from the human lung tumor A549 cells. The expression of this gene as a function of the cell cycle is being investigated after various radiation conditions. We plan to explore the role of rad9 in G2/M arrest and radiation sensitivity of human tumor cells.

Publications

1. Tsai, M.A., Waugh, R.E., and Keng, P.C., Cell cycle-dependence of HL-60 cell deformability. Biophys. J., 70 (1996) pp. 2023-2029. Masunaga, S., and Keng, P.C., Effects of caffeine on gamma-ray induced G2 arrest in well-synchronized Chinese hamster ovary cells in vitro. Radiat. Med. 14 (1996) pp. 309-313.
2. Wenz, F. Yu, Y. Nagasawa, H., Imrich, A.C., Keng, P.C., and Little, J.B., Lack of uncoupling of S phase and mitosis after irradiation in p53-human lymphoblast cell lines. Radiat. Res. 148(1997)pp.129-134.
3. Nagasawa, H., Keng, P.C., Maki, C., Yu, Y., and Little, J.B., Absence of a radiation-induced first-cycle G1-S arrest in p53+ human tumor cells synchronized by mitotic selection. Cancer Res. 58(1998) pp. 2036-201.
4. Keng, P.C., Siemann, D.W., Measurement of proliferation activities in human tumor models: a comparison of flow cytometric methods. Radiat. Oncol. Invest. 6(1998) pp.120-127.
5. Tsai, M.A., Waugh, R.E., Keng, P.C. Passive mechanical behavior of human neutrophils: effects of colchicine and paclitaxel. Biophysical Journal. 74(1998) pp.3282-91.
6. Georgakoudi, I., Keng, P.C., and Foster, T.H., Hypoxia significantly reduces aminolaevulinic acid-induced protoporphyrin IX synthesis in EMT6 cells. Brit. J. Cancer. (1999) pp.1372-1377.
7. deToledo, S.M., Azzam, E.I., Keng, P., Laffrenier, S., and Little, J.B., Regulation by ionizing radiation of cdc2, cyclin A, cyclin B, thymidine kinase, topoisomerase II and RAD51 expression in normal human diploid fibroblasts is dependent on p53/p21. Cell Growth & Differentiation. 9(1999) pp. 887-896.
8. Rancourt, R.C., Keng, P.C., Oreilly, M.A., Hyperoxia inhibits proliferation of Mv1Lu epithelial cells independent of transforming growth factor-beta. Am. J. Physiology: Lung Cellular and Molecular Physiology 277(1999) pp. L1172-L1178
9. O'Reilly, M., Staversky, R., Watkins, R., Maniscalco, W., and Keng, P.C., p53-independent induction of GADD45 and GADD153 in mouse lungs exposed to hyperoxia. Am. J. Physiol. Cell & Mole. Physiol. 278(2000) pp. L552-L559.
10. Lee, J., Moran, J.P., Fenton, B.M., Koch, C.J., Frelinger, J.G., Keng, P.C. and Lord, E.M., Alteration of tumor response to radiation by interleukin-2 gene transfer. Brit. J. Cancer. 82(2000) pp. 937-944.
11. Wheeler, K.T., Wang, L-M., Wallen, C.A., Childers, S.R., Cline, J.M., Keng, P.C., and Mach, R.H., Sigma-2 receptors as a biomarker of proliferation in solid tumours. Brit. J. Cancer. 82(2000) pp. 1223-1232. Chen, Y.G., Mantalaris, A., Bourne, P., Keng, P., Wu, D. Expression of mPer1 and mPer2, two mammalian clock genes, in murine bone marrow. Biochem. Biophy. Res.Commun. 26 (2000) pp. 724-728.
12. Rancourt, R., Keng, P.C., Helt, C., and O'Reilly, M., The role of p21 CIP1/WAF1 in growth of epithelial cells exposed to hyperoxia. Am. J. Physiol. Cell & Mole. Physiol 280 (2001) pp. L617-626.
13. O'Reilly, M.A., Staversky, R.J., Watkins, R.H., Reed, C.K., de Mesy Jensen, K.L., Finkelstein, J.N., and Keng, P.C. The cyclin-dependent kinase inhibitor p21 protects the lung from oxidative stress. Am. J. Respiratory: Cell and Molecular Biology 24(2001) pp.703-710.
14. Cao, Q., Abeysinghe, H., Chow, O., Xu, J., Kaung, H., Fong, C., Keng, P., Insel, R.A., Lee, W.M., Barrett, J.C., Wang, N. Suppression of tumorigenicity in human ovarian carcinoma cell line SKOV-3 by microcell-mediated transfer of chromosome 11. Cancer Genetics & Cytogenetics 129(2001) pp. 131-137.
15. Matsui, Y., Tsuchida, Y., and Keng, P.C., Effects of p53 mutations on cellular sensitivity to ionizing radiation. Am. J. Clinical Oncology 24(2001) pp. 486-490.
16. Chen, Y., Pandya, K., Keng, P.C., Raubertas, R., Smudzin, T., Rosenblatt, J., and Okunieff, P., Pulsed paclitaxel radiosensitization for thoracic malignancy: a therapeutic approach based on pre-clinical research of human lung cancer cells. Am. J. Clinical Oncology. (2001) pp. 432-437.
17. Rancourt, R.C., Hayes, D.D., Chess, P.R., Keng, P.C., O'Reilly, M.A. Growth arrest in G1 protects against oxygen-induced DNA damage and cell death. Journal of Cellular Physiology. 193(2002) pp26-36.
18. Baev, D., Li, X.S., Dong, J., Keng, P., Edgerton, M. Human salivary histatin 5 causes disordered volume regulation and cell cycle arrest in Candida albicans. Infection & Immunity. 70(2002) pp. 4777-84. O'Reilly, M.A., Staversky, R.J., Finkelstein, J.N., and Keng, P.C. Activation of the G2 checkpoint enhances survival of epithelial cells exposed to hyperoxia. Am J. Physiol. Lung Cell Mol Physiol. 284(2003) L368-L375.
19. Xing, L., Carlson, L., Story, B., Tai, Z., Keng, P.C., Siebenlist, U., and Boyce, B.F. Expression of either NF-kB p50 or p52 in osteoclast precursors is required for IL-1-induced bone response. J. Bone and Mineeral Res. 18(2003) pp. 260-269.
20. Chen, Y., Pandya, K., Keng, P.C., Johnstone, D., Li, J., Lee, Y., Smudzin, T., and Okunieff, P., Phase I/II clinical study of pulsed paclitaxel radiosensitization for thoracic malignancy: a therapeutic approach on the basis of preclinical research of human cancer cell lines. Clinical Cancer Res. 9(2003) pp969-975.
21. Abeysinghe, H.R.. Cao, Q., Xu, J., Pollock, S., Veyberman, Y., Guckert, N.L., Keng, P., Wang, N., THY1 expression is associated with tumor suppression of human ovarian cancer. Cancer Genetics & Cytogenetics 143(2003)pp.125-32.
22. Roper, J.M., Staversky, R.J., Finkelstein, J.N., Keng, P.C., and O'Reilly, M.A. Identification and isolation of mouse type II cells on the basis of intrinsic expression of enhanced green fluorescent protein. Am J Physiol Lung Cell Mol Physiol. 285(2003) pp. L691-700.
23. Helt, C.E., Staversky, R.J., Lee, Y.J., Bambara, R.A., Keng, P.C., and O'Reilly, M.A. The CDK and PCNA domains on p21 Cip1 both function to inhibit G1/S progression during hyperoxia. Am J Physiol Lung Cell Mol Physiol. (2003) In Press.
24. Mazzatti, D.J., Lee, Y., Helt, C.E., O'Reilly, M.A. and Keng, P.C. P53 modulates radiation sensitivity independent of p21 transcriptional activation. Am J. Clinical Oncology (2004) In Press.
25. Abeysinghe, H.R., Pollock, S.J., Guckert, N.L., Veyberman, Y., Keng, P.C., Halterman, M., Federoff, H.J., Rosenblatt, J.P., and Wang, N., The role of the Thy1 gene in human ovarian cancer suppression based on transfection studies. Cancer Genetics & Cytogenetics 149(2004) pp. 1-10.
26. Roper JM, Mazzatti DJ, Watkins RH, Maniscalco WM, Keng PC, O'Reilly MA. In vivo exposure to hyperoxia induces DNA damage in a population of alveolar type II epithelial cells. Am J Physiol Lung Cell Mol Physiol 286: L1045-L1054, 2004.
27. Mao W, Qin F, Iwai C, Vulapalli R, Keng PC, Liang C. Extracellular norepinephrine reduces neuronal uptake of norepinephrine by oxidative stress in PC 12 cells. Am J Physiol 287: H29-H39, 2004.
28. Chen MF, Wu CT, Chen YJ, Keng PC, Chen WC. Cell killing and radiosensitization by caffeic acid phenethyl ester (CAPE) in lung cancer cells. J Radiat Res 45: 253-260, 2004.
29. Mazzatti DJ, Lee YJ, Helt CE, O'Reilly MA, Keng PC. p53 modulates radiation sensitivity independent of p21 transcriptional activation. Am J Clin Oncol, 28: 43-50, 2005.
30. Helt CE, Cliby WA, Keng PC, Bambara RA, O'Reilly MA. Ataxia telangiectasia mutated (ATM) and ATM and Rad3-related protein exhibit selective target specificities in response to different forms of DNA damage. J Biol Chem, 280: 1186-1192, 2005
31. Lee YJ and Keng PC. Studying the effects of actin cytoskeletal destabilization on cell cycle by cofilin over-expression. Mol. Biotech, 31:1-10, 2005
32. McCollum G, Keng PC, States JC, and McCabe M. Arsenite delays progression through each cell cycle phase and induces apoptosis following G2/M arrest in U937 myeloid leukemia cells. J Pharmacology and Exp. Therapeutics, 313: 877-887, 2005.
33. Helt C, Wang W, Keng PC, and Bambara R. 9-1-1 complex involvement in DNA repair: evidence that DNA damage detection machinery participates in DNA repair. Cell Cycle, 4: 529-532, 2005.
34. Tsai M-H, Chen X, Chandramouli GVR, Chen Y, Yan H, Zhao S, Keng PC, Liber HL, Coleman CN, Mitchell JB, and Chuang, EY. Transcriptional responses to ionizing radiation reveal that p53R2 protects against radiation-induced mutagenesis in human lymphoblastoid cells. Oncogene, 1-11,October, 2005.
35. Chen, M., Keng, P.C., Lin., P-Y., Yang, C-T., Liao, S-K., and Chen, W-C., Caffeic acid phenethyl ester decreases acute pneumonitis after irradiation in vitro and in vivo. BMC Cancer 5:158-168, 2005     
36. Lee, Y.J., Sheu, T-J., and Keng, P.C. Enhancement of radiosensitivity in H1299 cancer cells by actin-associated protein cofilin. Biochem. Biophys. Res. Comm., 335:286-291, 2005.
37. Lee, Y.J., Mazzatti, D.J., Zhong, Y. and Keng, P.C. Inhibition of invasiveness in human lung cancer cell line H1299 by over-expression of cofilin. Cell Biol. International, 29:877-883, 2006.
38. Chen, M-F., Keng, P.C., Shau, H., Wu, C-T., Hu, Y-C., and Liao, S-K. and Chen, W.C., Inhibition of lung tumor growth and augmentation of radiosensitivity by decreasing peroxiredoxin I expression. Int. J. Rad. Oncol. Biol. Phys. 64:581-591, 2006.
39. Brandt, P.D., Helt, C.E., Keng, P.C., and Bambara, R.A., The rad9 protein enhances survival and promotes DNA repair following exposure to ionizing radiation. Biochem. Biophys. Res. Comm., 347:232-237, 2006.
40. Yao, Z., Li, P., Zhang, Q., Schwarz, E.M., Ma, L., Keng, P.C., Boyce, B.F., and Xing, L., TNF increases circulating osteoclast precursor numbers by promoting bone marrow osteoclast precursor proliferation and differentiation through up-regulation of c-Fms expression. J. Biol. Chem. 281 (2006) pp. 11846-11855.
41. Mao, W., Iwai, C., Keng, P.C., Raju, V., and Liang, C., Norepinephrine-induced oxidative stress causes PC-12 cell apoptosis by both endoplasmic reticulum stress and mitochondrial intrinsic pathway: inhibition of phosphatidylinositol 3-kinase survival pathway. Am. J. Physiology 290:C1373-C1384, 2006.
42. Staversky, R.J., Vitiello, P.F., Helt, C.E., Rahman, A., Keng, P.C., and O’Reilly, M.A. p21 Cip1/Waf1/Sdi1 protects against persistent oxidative stress by maintaining expression of Bcl-XL. Free Radical Biology and Medicine 41: 601-609, 2006.
43. Gehen, S.C., Vitiello, P.F., Bambara, R.A., Keng, P.C., and O’Reilly, M.A. Down-Regulation of PCNA Potentiates p21-Mediated Growth Inhibition in Response to Hyperoxia. Am J Physiol Lung Cell Mol Physiol. In Press, 2007.
44. Ghosh, A., Keng, P.C., and Knauf, P. Hypertonicity induced apoptosis in HL-60 cells in the presence of intracellular potassium. Apoptosis. In Press, 2007.