The present MERIT award continues the theme of understanding the activation and transformation by erbB family oncogenes and seeks to characterize the role of erbB2/HER/neu in prostate cancer biology. In the past grant period, significant progress has been made, which reveals that erbB2 in prostate cancer cells crosstalks not only with other erbB receptors, but also receptor for cytokine IL6. This interaction is functionally important, as inactivating erbB2 receptor leads to impaired IL6 induction of MAP kinase pathway and neuroendocrine differentiation (NED). This is the first time that erbB3 was found to be activated by a cytokine and that IL6, a potent stimulator, was found to induce NED of prostate cancer cells. NED of prostate cancers has been implicated in PCA progression and androgen independent state. Increasing evidence suggests that NE cells serve as paracrine source for the growth and migration of the surrounding tumor cells. Compared to other processes, the mechanisms of NED are understudied. Another discovery supported by this grant is the development of a tyrosine kinase display method which permits the identification of virtually all tyrosine kinases in a single PCR reaction and in a single gel. Dr. Kung therefore knows precisely all the tyrosine kinases expressed in a single PCA cell type. With this method, he uncovers a tyrosine kinase Etk in PCA which is critical in NED or PCA. The present proposal is based on the above three novel findings and intends to study: 1) the mechanisms involved in receptor cross talk between erbB2 and IL6 receptor and 2) the NED signal pathways mediated by erbB2 and Etk.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA039207-20
Application #
6696746
Study Section
Pathology B Study Section (PTHB)
Program Officer
Cole, John S
Project Start
1991-01-01
Project End
2005-12-31
Budget Start
2004-01-01
Budget End
2005-12-31
Support Year
20
Fiscal Year
2004
Total Cost
$311,099
Indirect Cost
Name
University of California Davis
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
Wu, Yi-Mi; Robinson, Dan R; Kung, Hsing-Jien (2004) Signal pathways in up-regulation of chemokines by tyrosine kinase MER/NYK in prostate cancer cells. Cancer Res 64:7311-20
Lee, Li-Fen; Louie, Maggie C; Desai, Sonal J et al. (2004) Interleukin-8 confers androgen-independent growth and migration of LNCaP: differential effects of tyrosine kinases Src and FAK. Oncogene 23:2197-205
Chen, Kai-Yun; Huang, Li-Ming; Kung, Hsing-Jien et al. (2004) The role of tyrosine kinase Etk/Bmx in EGF-induced apoptosis of MDA-MB-468 breast cancer cells. Oncogene 23:1854-62
Yustein, Jason T; Xia, Liang; Kahlenburg, J Michelle et al. (2003) Comparative studies of a new subfamily of human Ste20-like kinases: homodimerization, subcellular localization, and selective activation of MKK3 and p38. Oncogene 22:6129-41
Xia, Liang; Robinson, Dan; Ma, Ai-Hong et al. (2002) Identification of human male germ cell-associated kinase, a kinase transcriptionally activated by androgen in prostate cancer cells. J Biol Chem 277:35422-33
Tepper, Clifford G; Boucher, David L; Ryan, Philip E et al. (2002) Characterization of a novel androgen receptor mutation in a relapsed CWR22 prostate cancer xenograft and cell line. Cancer Res 62:6606-14
Lee, L F; Guan, J; Qiu, Y et al. (2001) Neuropeptide-induced androgen independence in prostate cancer cells: roles of nonreceptor tyrosine kinases Etk/Bmx, Src, and focal adhesion kinase. Mol Cell Biol 21:8385-97
Yustein, J T; Li, D; Robinson, D et al. (2000) KFC, a Ste20-like kinase with mitogenic potential and capability to activate the SAPK/JNK pathway. Oncogene 19:710-8
Jui, H Y; Tseng, R J; Wen, X et al. (2000) Protein-tyrosine phosphatase D1, a potential regulator and effector for Tec family kinases. J Biol Chem 275:41124-32
Tsai, Y T; Su, Y H; Fang, S S et al. (2000) Etk, a Btk family tyrosine kinase, mediates cellular transformation by linking Src to STAT3 activation. Mol Cell Biol 20:2043-54

Showing the most recent 10 out of 42 publications