Tyrosine kinases and oncogenic signals: Tyrosine kinases represent major class of oncogenes. Our laboratory has developed effective approaches to define tyrosine kinases differentially expressed in cancer cells and is studying how they are activated to drive the oncogenic signals in cancers such as prostate carcinoma. ErbB, Nyk, Ret and Etk are among the tyrosine kinases being investigated. Recent findings reveal that these kinases also play significant roles in the development of androgen-independence of the tumors. They do so by transmitting phosphorylation signals to androgen receptor or its coactivators, such that androgen receptor is activated without its ligand. Also under `study are novel serine kinases such as KFC and MAK which are integrators of the tyrosine kinase signals. The overall objectives are to define the mechanisms underlying the growth, apoptosis, differentiation and therapeutic responses of cancers. Given the significant promises of using tyrosine kinase inhibitor in cancer therapy, our studies also have strong translational value.

Molecular genetics of oncogenic viruses: Marek's disease herpesvirus (MDV) and Kaposi's sarcoma herpesvirus (KSHV) are both oncogenic viruses, each encoding a bZIP protein (i.e., MDV Meq and KSHV KbZIP). Our laboratory has identified both of them and we are studying their molecular actions. For MDV, Meq-null mutant has been developed and its replication and oncogenicity studies are being conducted. The results strongly suggest that Meq is the oncoprotein of Marek's disease virus. Meq, in many aspects, behaves very much like jun oncogene and is likely to use the cellular jun pathway in transformation. The KHSV bZIP protein, on the other hand, seems to be more involved in viral replication and transcriptional repression. In addition, these viruses encode virokines (e.g., MDV v-IL-8 and KSHV v-IL-6). Understanding how virokines enhance viral replication and recruit target cells is another topic being studied in the laboratory.

Selected Publications: Lee LF, Liu JL, Cui XP, Kung HJ. Marek's disease virus latent protein MEQ: delineation of an epitope in the BR1 domain involved in nuclear localization. Virus Genes (in press) 2003

Gwack Y, Nakamura H, Lee SH, Souvlis J, Gygi S, Kung HJ and Jung JU. PARP-1 and Ste20-like hKFC act as transcriptional repressors for gamma-2 herpesviral lytic replication. Mol. Cell Biol. (in press) 2003

Levy AM, Izumiya Y, Brunovskis P, Xia L, Parcells MS, Reddy SM, Lee L, Chen HW, and Kung HJ. Characterization of the chromosomal binding sites and dimerization partners of the viral oncoprotein Meq in Marek's Disease Virus transformation T-cells. J. Virol, in press. (2003)

Izumiya Y, Kung HJ. Cell cycle regulation by KSHV K-bZIP: Direct interaction with cyclin-CDK2 and induction of G1 growth arrest. J. Virol. 77: 9652 (2003)

Yang HQ, Louie MC, Ma AH, Zou JX, Kung HJ, and Chen HW. Androgen-dependent direct recruitment of RNA polymerase II at the enhancer via androgen receptor-p160 coactivator complex. Proc. Natl. Acad. Sci., 100: 2226-30 (2003).

Izumiya Y, Lin SF, Ellison T, Chen LY, Izumiya C, Luciw P and Kung HJ. Kaposi's sarcoma-associated herpesvirus K-bZIP is a co-regulator of K-Rta: physical association and promoter-dependent transcriptional repression. J. Virol. 77(2): 1441-1451 (2003)

Yustein JT, Xia L, Kahlenburg JM, Robinson D, Templeton D, and Kung HJ. Comparative studies of a new subfamily of human Ste20-like kinases: homodimerization, subcellular localization and selective activation of MKK3/p38MAPK. Oncogene in press (2003)

Liao W, Tang Y, Lin SF, Kung HJ, and Giam CZ. K-bZIP of Kaposi's Sarcoma-Associated Herpesvirus/Human Herpesvirus type 8 Binds KSHV/HHV-8 Rta and Represses Rta-Mediated Transactivation. J. Virol. 77: 3809-3815 (2003)

Huang CYF, Wu YM, Hsu CY, Lee WS, Lai MD, Lu TJ, Huang CL, Leu TH, Shih HM, Fang HI, Robinson DR, Kung HJ, and Yuan CJ. Caspase activation of mammalian sterile 20-like kinase 3 (Mst3): Nuclear translocation and induction of apoptosis. J. Biol. Chem. 227:(37):34367-74 (2002)

Xia L, Robinson D, Ma AH, Chen HC, Wu F, Qiu Y and Kung HJ. Identification of hMak, a kinase transcriptionally activated by androgen in prostate cancer cells. J. Biol. Chem. 277(38):35422-35433 (2002)

Zhou H, Liu L, Lee K, Qin X, Grasso AW, Kung HJ, Willis JE, Kern J, Wagner T and Gerson SL. Lung tumorigenesis associated with erbB-2 and erbB-3 overexpression in human erbB3 transgenic mice is enhanced by methylnitrosourea. Oncogene 21: 8732-8740 (2002)

Lin SF, Robinson DR, Oh J, Jung JU, Luciw PA, and Kung HJ. Identification of the bZIP and Rta homologues in the genome of Rhesus monkey rhadinovirus (RRV). Virology, 298(2):181-188 (2002)

Davidson I, Borenshtain R, Kung HJ, Witter RL. Molecular indications for in vivo integration of the avian leukosis virus, subgroup J-long terminal repeat into the Marek's disease virus in experimentally dually-infected chickens. Virus Genes. Mar;24(2):173-80 (2002)

Shi, XB, Ma AH, , Xia L, Kung HJ, and de Vere White RW. Prostate cancer-derived mutant androgen receptors. Cancer Res. 62:1496-502 (2002)

Tepper CG, Boucher DL, Ma AH, Xia L, Lee LF, Pretlow TG and Kung HJ. Identification of a novel androgen receptor mutation in a relapsed CWR22 prostate cancer xenograft and cell line. Cancer Res. 62:6606-6614 (2002)

Lee LF, Guan JL, Qiu Y and Kung HJ. Neuropeptide-induced androgen independence in prostate cancer cells: the roles of non-receptor tyrosine kinases Etk/Bmx, Src and FAK. Mol. Cell Biol. 21:8385-8397(2001)

Bostik P, Wu P, Dodd GL, Villinger F, Mayne AE, Bostik V, Grimm BD, Robinson D, Kung HJ and Ansari AA. Identification of protein kinases dysregulated in CD4(+) T cells in pathogenic versus apathogenic simian immunodeficiency virus infection. J. Virol. 75:11298-11306 (2001)

Lin JL, Chen HC, Fang HI, Robinson D, Kung HJ and Shih HM MST4, a new Ste 20-related kinase that mediates cell growth and transformation via modulating ERK pathway. Oncogene 20:6559-69 (2001)

Liu HC, Kung HJ, Fulton JE, Morgan RW and Chen HH. Growth hormone interacts with the Marek's disease virus SORF2 protein and is associated with disease resistance in chicken PNAS 98:9203-9208 (2001)

Chen, R, Kim , O, Li, M, Ilic, D, Xioing, X, Guan, JL, Kung HJ, Chen H, Damsky, CH, Shimizu, Y and Qiu, Y. Regulation of a PH-domain-containing tyrosine kinase Etk by focal adhesion kinase through the FERM domain. Nature Cell Biol. 3:439-444, (2001)

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