Kuang Yu Chen Professor Rutgers University Department of Chemistry Wright Lab Room A108 Busch Campus (732) 445-3739 FAX - 5312 kychen@rutchem.rutgers.edu

Hypusine formation and eukaryotic initiation factor 5A; nutraceuticals-genomic screening and interactions; cell aging and late G1 gene regulation; osmotic stress and heat shock factor activation

Hypusine Project:

The eukaryotic initiation factor 5A is the only protein known to contain a hypusine residue. an unusual amino acid formed by the action of deoxyhypusine synthase and deoxyhypusine hydroxylase using spermidine as the substrate. Although genes encoding eIF-5A and deoxyhypusine synthase are essential for cell survival and proliferation. the function of eIF-5A is unknown. We have generated almost all the molecular tools to study the biochemistry and function of eIF-5A and the significance of its hypusine formation. The biological systems used are mammalian cells. yeast. and C.elegans.

Cancer Biology Project:

There are three focuses: (i) Systematic screening of food chemicals and nutraceuticals isolated from plants that are anti-proliferative. anti-inflammatory. or pro-apoptotic. We are particularly interested in nutraceuticals that may modulate or inhibit important or disease-related genes such as NF-kB. p53. ornithine decarboxylase. and cyclooxygenase 2 (Cox-2). either at transcriptional or translational level. Novel methodologies. including microarray. are being developed to perform these screenings. (ii) Design and synthesis of compounds targeting at polyamine network. including hypusine formation. High polyamine content has known to be associated with many cancer types. (iii) Design and synthesis natural product-based compounds that possess clear and enhanced differential growth inhibitory effect against tumor cells in vitro and in vivo.

Cellular Aging Project:

The hallmark of cell aging is the loss of dividing potential in normal cells during senescence. A global change of expressions of G1/S genes in human diploid cells during aging process. which ensures limited lifespan of normal cells. Our current focuses are: (i) the role of NF-Y and E2F on this global change and (ii) screening for small molecules that can modulate the lifespan of cells.

Osmosis Stress Project

Similar to heat stress. osmotic stress activates HSF1. Unexpectedly. both hypo- and hyper-osmotic stress produce similar activation. We are studying the mechanism and physiological significance of this intriguing phenomenon.

Selected Publications

Gosslau A, Pabbaraja S, Knapp S, Chen KY. (2008) Trans- and cis-stilbene polyphenols induced rapid perinuclear mitochondrial clustering and p53-independent apoptosis in cancer cells but not normal cells. Eur J Pharmacol. 587(1-3):25-34.

Oza J, Yang J, Chen KY, Liu AY. (2008) Changes in the regulation of heat shock gene expression in neuronal cell differentiation. Cell Stress Chaperones. 13(1):73-84.

Yang J, Oza J, Bridges K, Chen KY, Liu AY. (2008) Neural differentiation and the attenuated heat shock response. Brain Res. 1203:39-50.

Jao. D.L. and Chen. K.Y. (2006) Tandem affinity purification revealed the hypusine-dependent binding of eukaryotic initiation factor 5A to the translating 80S ribosomal complex. J. Cell. Biochem. 97:583-598.

Chatterjee. I.. Gross. S.R. Kinzy. T.G. and Chen. K.Y. (2006) Rapid depletion of mutant eukaryotic initiation factor 5A at restrictive temperature reveals connections to actin cytoskeleton and cell cycle progression. Mol. Genet. Genomics 275:264-276.

Gosslau. A.. Chen. M.. Ho. C.-T. and Chen. K.Y. (2005) A methoxy derivative of resveratrol analog exhibits potent and striking differential growth inhibitory effect against human cancer cells. British J. Cancer 92:13-521.

Fang. F.. Sang. S.. Chen. K.Y.. Gosslau. A.. Ho. C.-T.. and Rosen. R.T. (2005) Isolation and identification of cytotoxic compounds from bay leaf (Laurus nobilis). Food Chem. 93:497-501.

Gosslau. A. and Chen. K.Y. (2004) Nutraceuticals. apoptosis. and disease prevention. Nutrition 20:95- 102.

Xu. A.. Jao. D.L. and Chen. K.Y. (2004) Identification of mRNA that binds to eukaryotic initiation factor 5A by affinity co-purification and differential display. Biochemical Journal 384:585-590.

Matuoka. K.. Chen. K.Y. and Takenawa. T. (2003) A positive role of phosphatidylinositol 3-kinase in aging phenotype expression in cultured human diploid fibroblasts. Archives Gerontology and Geriatrics 36: 203-219.

Jao. D.L. and Chen. K.Y. (2002) Subcellular localization of the hypusine-containing eukaryotic initiation factor 5A by immunofluorescent staining and Green Fluorescent protein tagging. J. Cell. Biochem. 86: 590-600.

Matuoka. K. and Chen. K.Y. (2002) Transcriptional regulation of cellular senescence by the CCAAT box-binding proteins CBF/NF-Y. Aging Research Reviews 1: 639-651.

Xu. A. and Chen. K.Y. (2001) Hypusine is required for a sequence-specific interaction of eukaryotic initiation factor 5A with post-SELEX RNA. J. Biol Chem. 276:2555-2561.

Lu. J.B.. Ho. C.-T. . Ghai. G. and Chen. K.Y. (2001) Resveratrol analog. 3. 4. 4'. 5-tetrahydroxystilbene. differentially induces pro-apoptotic p53/Bax gene expression and inhibits the growth of transformed cells but not their normal counterparts. Carcinogenesi 22:321-328.

Chen. K.Y.. Lu. Jiebo and Liu. A.Y.-C. (2000) The activation of trans-acting factors in response to hypo- and hyper-osmotic stress in mammalian cells. in "Environmental Stressors and Gene Responses" (eds. Storey. K. and Storey. J). Elsevier Press. Amsterdam. pp. 141-155.

Lu. J.B.. Park. J.. Liu. A.Y-C. and Chen. K.Y. (2000) Osmotic stress-induced activation of HSF1 DNA binding activity is dramatically attenuated in senescent human cells. J. Cell. Physiol. 184:183-190.

Matuoka. K. and Chen. K.Y. (2000) Possible role of subunit A of nuclear factor Y (NF-Y) in normal human diploid fibroblasts during senescence. Biogerontology 1: 261-271.

Lu. J.B.. Ho. C.-T. . Ghai. G. and Chen. K.Y. (2000) Differential effects of theaflavin monogallates on cell growth. apoptosis and Cox-2 gene expression in cancerous versus normal cells. Cancer Research 60:6465-6471.

Lu. J.. Chen. Z.P.. Yan. Y.P.. Knapp. S.. Schugar. H. and Chen. K.Y. (2000) 6-Aminohexanoic hydroxamate is a potent inducer of the differentiation of mouse neuroblastoma cells. Cancer Lett. 160:59-66.