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Toledo, OH 43614
Kam C. Yeung, Ph.D.
Beach, S., Tang, H., Park, S., Dhillon, A.S., Keller, E.T., Kolch, W. and Yeung, K.C.
(2008) Snail is a repressor of RKIP transcription in metastatic prostate cancer cells. Oncogene, 27:2343-2348.
The major focus of our research program is to understand the molecular basis of cell signaling on cellular as well as organismal levels. In metazoan each individual cell is related to others by the interplay of numerous signaling pathways. Dyregulation of signaling pathways often affects cellular homeostasis leading to different pathological conditions including cancers. Ongoing projects include:
1. Regulation of RKIP protein interaction network
The project focuses on elucidating the function of Raf Kinase Inhibitor Protein, RKIP, a novel kinase inhibitor that was identified as a potent tumor metastasis suppressor. Mechanistically, this protein functions as a negative regulator of both the Raf and NF-kB signaling pathways. In this project we will investigate three possible mechanisms of RKIP regulation. We will investigate in detail the mechanism of RKIP regulation by phosphorylation. The in vivo phosphorylation status of RKIP will be examined under a variety of physiological conditions known to stimulate MAPK activity. We will examine the effects of phosphorylation on the biological activities of RKIP towards its known targets. Several lines of evidence indicate that RKIP contains a novel phospho amino acid binding motif. We showed that RKIP bounds to phosphorylated residues on Raf-1. We will investigate whether the phosphorylation/dephosphorylation of RKIP targets is a general mechanism that governs RKIP interaction with its molecular partners. Finally we have identified TRAF6 as a putative mediator of RKIP effect on NK-kB activation. A combination of biochemical and genetics approach will be used to confirm its mediator function in vivo.
2. RKIP regulation as a potential for tumor suppression
Consistent with its inhibitory effects on the Raf and NF-kB signaling pathways, a significant inverse correlation was observed between the expression of RKIP and the stage of cancer development in prostate tumors. Importantly, restoration of RKIP expression in highly metastatic prostate cancer cell lines sensitized them to apoptosis and inhibited metastasis in a xenograft mouse model, suggesting this protein as a promising candidate for cancer therapy. In order to exploit this potential, this project proposes to define the transcription factors that regulate RKIP expression and establish its tumor metastasis suppression function in vivo. Moreover, we will use tissue microarray (TMA) studies to determine the relationship of the expression of RKIP to the putative regulators of RKIP expression in samples from prostate cancer patients. We will also study in more depth the in vivo role of RKIP as a tumor metastasis suppressor, by exploring whether RKIP deficiency is essential for or facilitates prostate cancer progression and metastasis in transgenic mice.
B.Sc. 1986 Basic Medical Sciences, University of South Alabama, Mobile, AL
Ph.D. 1990 Microbiology, University of South Alabama, Mobile, AL
1990 - 1992 Post-Doc, Molecular Virology, University of Iowa, Iowa City, IA
1992 - 1996 Post-Doc, Biochemistry, Howard Hughes Medical Institute/UMDNJ, Piscataway, NJ
2009-pre Associate Professor, Biochemistry & Cancer Biology, University of Toledo College of Medicine & Life Sciences, Toledo, OH
2001-2009 Assistant Professor, Biochemistry & Cancer Biology, University of Toledo Health Science Campus, Toledo, OH
1996-2001 Research Assistant Professor, Dept. of Molecular Biology, Cell Biology & Biochemistry, Brown University, Providence, RI
Escara-Wilke, J., Keller, J.M., Woods Ignatoski, K.M., Dai, J., Shelley, G., Mizokami, A., Zhang, J., Yeung, M.L., Yeung, K.C. and Keller, E.T. (2014) Raf kinase inhibitor protein (RKIP) deficiency decreaes latency of tumorigenesis and increases metastasis in a murine genetic model of prostate cancer. Prostate 2014 Oct 18. doi: 10.1002/pros.22915. [Epub ahead of print]
Datar, I., Tegegne, H., Qin, K., Al-Mulla, F., Bitar, M.S., Trumbly, R.J., and Yeung, K.C. (2014) Gentic and epigenetic control of RKIP transcription. Crit. Rev. Oncogen. 19:417-430.
Marathe, H.G., Mehta, G., Zhang, X., Datar, I., Mehrotra, A., Yeung, K.C. and de la Serna, I.L. (2013) SWI/SNF enzymes promote SOX10-mediated activationof myelin gene expression. PLoS One 8:e69037.
Al-Mulla, F., Bitar, M.S., Al-Ali, Zainab, T., and Yeung, K.C. (2013) RKIP: Much more than Raf kinase inhibitory protein. J Cell Phys 228:1688-1702.
Ren, G., Feng, J., Datar, I., Yeung, A.H., Saladi, S.V., Feng, Y., de la Serna, I., and Yeung, K.C. (2012) A micro-RNA connection in BRaf(V600E)-mediated premature senescence of human melanocytes. Int. J. Cell Biol. 2012:913242.
Escara-Wilke, J., Yeung, K.C., and Keller, E.T. (2012) Raf kinase inhibitor protein (RKIP) in cancer. Cancer Metastasis Rev 31:615-620.
Zhang, H., Wu, J., Keller, J.M. Yeung, K.C., Keller, T.T., and Fu, Z. (2012) Transcriptional regulation of RKIP expression by androgen in prostate cells. Cell Physiol. Biochem. 30:134-1350.
Al-Mulla, F., Bitar, M.S., Feng, J., Park, S., and Yeung, K.C. (2012) A new model for raf kinase inhibitory protein induced chemotherapeutic resistance. PLoS 7:e29532
Ren, G., Feng, J., Datar, I., Yeung, A.H., Saladi, V., Feng, Y., de la Serna, I., and Yeung, K.C. (2011) A micro-RNA connection in BRafV600E-mediated premature senescence of human melantocytes. Int J Cell Biol 2012:913242
Park, S., Tang, H., and Yeung, K.C. (2011) A dual role of RKIP in NF-kB signaling pathways, Forum on Immunopathological Diseases and Therapeutics 2: 21-34.
Ren, G., Baritaki, S., Marathe, H., Feng, J., Park, S., Beach, S., Bazeley, P., Beshir, A.B., Fenteany, G., Mehra, R., Daignault, S., Al-Mulla, F., Keller, E., Bonavida, B., de la Serna I., and Yeung, K.C. (2011) Polycomb protein EZH2 regulates tumor invasion via the transcriptional repression of the metastasis suppressor RKIP in breast and prostate cancer. Cancer Res 72:3091-3014.
Tang, H., Park, S., Sun, S.C. Trumbly, R., Ren, G., Tsung, E., and Yeung, K.C. (2010) RKIP inhibits NF-kB in cancer cells by regulating upstream signaling components of the IkappaB kinase complex. FEBS Lett 584:662-668.
Beshir, A.W., Ren, G., Magpusao, A.N., Barone, L.M., *Yeung, K.C., and *Fenteany, G. (2010) Raf kinase inhibitor protein suppresses nuclear factor-kB dependent cancer cell invasion at the level of matrix metalloproteinase expression but not cell migration. Cancer Lett 299:137-149. *co-corresponding authors.
Baritaki, S., Yeung, K.C., Palladino, M., Berenson, J.M., and Bonavida, B. (2009) Pivotal roles of snail inhibition and RKIP induction by the proteasome inhibitor NPI-0052 in tumor cell chemo- immuno-sensitization. Cancer Res 2009: 69:8376-8385.
Tang, H., Yeung, K.C. (2008) TAK1 (TGFß-Activating Kinase 1) Atlas Genet Cytogenet Oncol Haematol. URL: http://AtlasGeneticsOncology.org/Genes/MAP3K7ID44ch6q15.html
McHenry, K., Montesano, R., Zhu, S., Beshir, A.B., Tang, H., Yeung, K.C. and Fenteany, G. (2008) Raf kinase inhibitor protein positively regulates cell-substratum adhesion while negatively regulating cell-cell adhesion. J. Cell. Biochem. 103(3):972-985.
Rath, O., Park, S., Tang, H.H., Banfield, M.J., Brady, R.L., Lee, Y.C., Dignam, J.D., Sedivy, J.M., Kolch, W. and Yeung, K.C. (2008) The RKIP (Raf-1 Kinase Inhibitor Protein) conserved pocket binds to the phosphorylated N-region of Raf-1 and inhibits the Raf-1-mediated activated phosphorylation of MEK. Cell Signal, 20:935-941.
Bonavida, S., Baritaki, S., Huerta-Yepez, S., Vega, M.I., Chatterjee, D. and Yeung, K.C. (2008) Novel therapeutic applications of Nitric Oxide donors in cancer: roles in chemo- and immuno-sensitization to apoptosis and inhibition of metastases. Nitric Oxid: Biology and Chemistry, 19:152-157.
Theroux, S., Pereira, M., Casten, K.S., Burwell, R.D., Yeung, K.C., Sedivy, J.M. and
Klysik, J. (2007) Raf kinase inhibitory protein knockout mice: Expression in the brain and olfaction
deficit. Brain Res. Bull. 71(6):559-567.
Baritaki, S., Katsman, A., Chatterjee, D., Yeung, K.C, Spandidos, D.A. and Bonavida, B. (2007) Regulation of tumor cell sensitivity to TRAIL-induced apoptosis by the metastatic supppressor RKIP via YY1 inhibition and DR4 up-regulation. J. Immun., 179(8):5441-5453.
Park, S., Rath, O., Beach, S., Xiang, X., Kelly, S.M., Luo, Z., Kolch, W. and Yeung, K.C. (2006) Regulation of RKIP binding to the N-region of Raf-1 kinase. FEBS Lett. 580(27):6405-6412.
Hindley, A.D., Park, S., Wang, L., Shah, K., Wang, Y., Hu, X., Shokat, K.M., Kolch, W., Sedivy, J.M. and Yeung, K.C. (2004) Engineering the serine/threonine protein kinase Raf-1 to utilize an orthogonal analogue of ATP substituted at the N6 position. FEBS Lett. 556:26-34.
Chatterjee, D., Bai, Y., Wang, Z., Beach, S., Mott, S., Roy, R., Braastad, C., Sun,
Y., Mukhopadhyay, A., Aggarwal, B.B., Darnowski, J., Pantazis, P., Wyche, J., Fu,
Z., Kitagwa, Y., Keller, E.T., Sedivy, J.M. and Yeung, K.C. (2004) RKIP sensitizes cancer cells to apoptosis. J. Biol. Chem. 279:17515-17523.
Keller, E.T., Fu, Z., Yeung, K.C. and Brennan, M. (2004) Raf kinase inhibitor protein: A prostate cancer metastasis suppressor gene. Cancer Lett. 30:131-137.
Odabaei, G., Chatterjee, D., Jazirehi, A.L., Goodglick, L., Yeung, K.C. and Bonavida, B. (2004) Raf-1 kinase inhibitor protein (RKIP): Structure, function, regulation of cell signaling and pivotal role in apoptosis. Advances in Cancer Research 91:169-200.
Park, S., Yeung, M., Beach, S., Shield, J. and Yeung, K.C. (2004) RKIP down-regulates B-Raf kinase activity in melanoma cancer cells. Oncogene 24:3535-3540.
Chatterjee, D., Schmitz, I., Krueger, A., Yeung, K.C., Kirchoff, S., Krammer, P.H.,
Peter, M.E., Wyche, J.H. and Pantazis, P. (2001). Induction of apoptosis in 9-nitrocamptothecin-treated DU145 human prostate carcinoma
cells correlates with de novo synthesis of CD95 and CD95 ligand and down-regulation
of c-FLIPshort. Cancer Res. 61:7148-7154.
Yeung, K.C., Rose, D.W., Dhillon, A.S., Yaros, D., Gustafsson, M., Chatterjee, D., McFerran, B., Wyche, J., Kolch, W. and Sedivy, J.M. (2001). Raf kinase inhibitor protein interacts with NF-kB-inducing kinase and TAK1 and inhibits NF-kB activation. Mol. Cell. Biol. 21:7207-7217.
Yeung, K.C., Janosch, P., McFerran, B., Rose, D., Mischak, H., Sedivy, J.M. and Kolch, W. (2000). The mechanism of suppression of the Raf/MEK/ERK pathway by the RKIP inhibitor protein. Mol. Cell. Biol. 20:3079-3085.
Yeung, K.C., Seitz, T., Li, S., Janosch, P., McFerran, B., Kaiser, C., Fee, F., Katsanakis, K.D., Rose, D.W., Mischak, H., Sedivy, J.M. and Kolch, W. (1999). Suppression of Raf-1 kinase activity and MAP kinase signaling by RKIP. Nature 401:173-177.