Abstract

The overall objective of this application is to define the functional role of protein kinase C (PKC) isoenzymes in TPA-induced transactivation of the ornithine decarboxylase (ODC) gene, and in TPA-induced tumor promotion in mouse epidermis. The principal investigator hypothesizes that PKC isoforms (, (1 and ( exhibit functional differences in TPA signals to ODC gene expression and tumor promotion, and that this functional divergence of PKC isozymes is the result of differences in the activation of the PKC downstream protein kinase MAPK. To test this hypothesis, the following aims will be carried out.
Aim 1. A difference in the role of PKC isoforms in TPA-induced ODC transcription and tumor promotion will be evaluated both by overexpression of the individual isoforms, as well as by attenuation of their activity by expression of dominant negative mutants, using two model systems: (a) the mouse epidermal promotion sensitive cell line (JB6 P+) in vitro; (b) intact mouse skin in vivo, using transgenic mice in which expression of a particular PKC isoenzyme.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA035368-15
Application #
2856239
Study Section
Chemical Pathology Study Section (CPA)
Program Officer
Okano, Paul
Project Start
1983-07-01
Project End
2000-12-31
Budget Start
1999-01-01
Budget End
1999-12-31
Support Year
15
Fiscal Year
1999
Total Cost
Indirect Cost

  Institution

Name
University of Wisconsin Madison
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715

  Publications

Hafeez, Bilal Bin; Meske, Louise; Singh, Ashok et al. (2016) Tissue-specific conditional PKC? knockout mice: a model to precisely reveal PKC? functional role in initiation, promotion and progression of cancer. Oncotarget 7:33069-80
Singh, Anupama; Singh, Ashok; Sand, Jordan M et al. (2015) Topically applied Hsp90 inhibitor 17AAG inhibits UVR-induced cutaneous squamous cell carcinomas. J Invest Dermatol 135:1098-1107
Hafeez, Bilal Bin; Jamal, Mohammad Sarwar; Fischer, Joseph W et al. (2012) Plumbagin, a plant derived natural agent inhibits the growth of pancreatic cancer cells in in vitro and in vivo via targeting EGFR, Stat3 and NF-?B signaling pathways. Int J Cancer 131:2175-86
Sand, Jordan M; Bin Hafeez, Bilal; Jamal, Mohammad Sarwar et al. (2012) Plumbagin (5-hydroxy-2-methyl-1,4-naphthoquinone), isolated from Plumbago zeylanica, inhibits ultraviolet radiation-induced development of squamous cell carcinomas. Carcinogenesis 33:184-90
Sand, Jordan Marshall; Bin Hafeez, Bilal; Aziz, Moammir Hasan et al. (2012) Ultraviolet radiation and 12-O-tetradecanoylphorbol-13-acetate-induced interaction of mouse epidermal protein kinase Cýý with Stat3 involve integration with ERK1/2. Mol Carcinog 51:291-302
Hafeez, Bilal Bin; Zhong, Weixiong; Weichert, Jamey et al. (2011) Genetic ablation of PKC epsilon inhibits prostate cancer development and metastasis in transgenic mouse model of prostate adenocarcinoma. Cancer Res 71:2318-27
Aziz, M H; Hafeez, B B; Sand, J M et al. (2010) Protein kinase Cvarepsilon mediates Stat3Ser727 phosphorylation, Stat3-regulated gene expression, and cell invasion in various human cancer cell lines through integration with MAPK cascade (RAF-1, MEK1/2, and ERK1/2). Oncogene 29:3100-9
Sand, Jordan M; Aziz, Moammir H; Dreckschmidt, Nancy E et al. (2010) PKCepsilon overexpression, irrespective of genetic background, sensitizes skin to UVR-induced development of squamous-cell carcinomas. J Invest Dermatol 130:270-7
Aziz, Moammir Hasan; Sundling, Kaitlin Elizabeth; Dreckschmidt, Nancy Ellen et al. (2009) Protein kinase Cepsilon inhibits UVR-induced expression of FADD, an adaptor protein, linked to both Fas- and TNFR1-mediated apoptosis. J Invest Dermatol 129:2011-21
Aziz, Moammir H; Dreckschmidt, Nancy E; Verma, Ajit K (2008) Plumbagin, a medicinal plant-derived naphthoquinone, is a novel inhibitor of the growth and invasion of hormone-refractory prostate cancer. Cancer Res 68:9024-32

Showing the most recent 10 out of 47 publications