Our research objective is to understand the molecular and genetic mechanisms responsible for cell growth, differentiation and neoplastic transformation. We study the oncogenes, tumor-suppressor genes and signal-transducing proteins involved in BALB/c mouse plasmacytomas, B-cell lymphomas and other mouse and human experimental tumor systems. These are valuable experimental models, because they can be used to devise more specific therapy and preventive measures for human multiple myeloma, non-Hodgkin's lymphomas, and other human malignancies. BALB/c plasmacytomas, like human Burkitt lymphomas, are characterized by constitutive expression of messenger RNA and protein from the master oncogene, c-Myc. It is still not clear which additional genetic alterations are required for complete transformation. We are using microarray hybridization studies of global gene expression to follow changes in gene expression duting progression from premalignant to fully malignant plasma cell tumors.In the study of signal transduction, we are investigating the isoform-specific features of protein kinase C (PKC), a multigene family of serine/threonine kinases that are important mediators of many forms of signal transduction. We have been focusing on the delta and epsilon isoenzymes, which have opposing effects on cell proliferation. We have shown that most of the isoenzyme-specific determinants are located in the catalytic half (the carboxyl-terminal domain) of these PKCs by creating reciprocal chimeric cDNAs that encode molecules that are half PKC-delta and half PKC-epsilon. We are further dissecting the structure of the catalytic domain to determine which sub-domains determine PKC isoform- specific functions, focusing on the carboxy-terminal 50 amino acids, the """"""""V5 domain."""""""" We are also studying the nature of PKC's involvement in apoptosis, in cytoskeleton-related changes in cell shape and motility, and in metastasis of these and other types of tumors, including human prostate cancer. We have shown that phorbol ester-activation of overexpressed PKC-delta disrupts the actin cytoskeleton in human and mouse lymphocytes, leading to the loss of membrane ruffling, a surface alteration needed for cell movement, and the loss of the typical elongated shape of these cells. We think that this effect is due to PKC-mediated changes in the phosphorylation of the adaptor molecule, paxillin.

National Institute of Health (NIH)
Division of Basic Sciences - NCI (NCI)
Intramural Research (Z01)
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Basic Sciences
United States
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Park, Eun Sung; Lee, Ju-Seog; Woo, Hyun Goo et al. (2007) Heterologous tissue culture expression signature predicts human breast cancer prognosis. PLoS One 2:e145
Wang, Hongyang; Owens, James D; Shih, Joanna H et al. (2006) Histological staining methods preparatory to laser capture microdissection significantly affect the integrity of the cellular RNA. BMC Genomics 7:97
Thiefes, Axel; Wolter, Sabine; Mushinski, J Frederic et al. (2005) Simultaneous blockade of NFkappaB, JNK, and p38 MAPK by a kinase-inactive mutant of the protein kinase TAK1 sensitizes cells to apoptosis and affects a distinct spectrum of tumor necrosis factor [corrected] target genes. J Biol Chem 280:27728-41
Park, Sung Sup; Kim, Joong Su; Tessarollo, Lino et al. (2005) Insertion of c-Myc into Igh induces B-cell and plasma-cell neoplasms in mice. Cancer Res 65:1306-15
Romanova, Larisa Y; Hashimoto, Shigeru; Chay, Kee-Oh et al. (2004) Phosphorylation of paxillin tyrosines 31 and 118 controls polarization and motility of lymphoid cells and is PMA-sensitive. J Cell Sci 117:3759-68
Wang, Qiming Jane; Lu, Ganwei; Schlapkohl, Walter A et al. (2004) The V5 domain of protein kinase C plays a critical role in determining the isoform-specific localization, translocation, and biological function of protein kinase C-delta and -epsilon. Mol Cancer Res 2:129-40
Mai, Sabine; Mushinski, J Frederic (2003) c-Myc-induced genomic instability. J Environ Pathol Toxicol Oncol 22:179-99
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Kuschak, T I; Taylor, C; McMillan-Ward, E et al. (1999) The ribonucleotide reductase R2 gene is a non-transcribed target of c-Myc-induced genomic instability. Gene 238:351-65
Romanova, L Y; Alexandrov, I A; Blagosklonny, M V et al. (1999) Regulation of actin cytoskeleton in lymphocytes: PKC-delta disrupts IL-3-induced membrane ruffles downstream of Rac1. J Cell Physiol 179:157-69

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