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Blanke, Kristina
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Sand, Jordan
 Jordan Sand - Email
PhD Candidate - Started 2005
Hails from North Dakota
Lab of Ajit Verma, PhD
Undergraduate Work
North Dakota State University-Fargo
Bachelor or Science, Microbiology & Biotechnology (2005)
Research as of 2008
The objectives of this proposal are to determine how protein kinase C epsilon (PKCe) sensitizes skin to ultraviolet radiation (UVR) or 12-O-tetradecanoyl-phorbol-13-acetate (TPA)-induced constitutive activation of Stat3 as well as the development of squamous cell carcinoma (SCC) (1,2). Constitutive activation of Stat3 is an important component of the mechanism of skin tumor promotion (3,4) and is associated with the development of human cancers including SCC (5,6). SCC, the non-melanoma form of human skin cancer, can be metastatic (7,8). Chronic exposure to UVR is the major etiologic factor linked to the development of SCC (9-13). We have previously reported that PKCe levels in mouse epidermis dictates the susceptibility of mice to the development of SCC by either DMBA-TPA protocol or repeated UVR exposures. As compared to wild-type littermates, PKCe overexpressing transgenic mice, either on FVB/N or SKH background, exhibited increased SCC incidence at least by 3-fold and decreased tumor latency by 12 weeks (14).
Recently, our laboratory discovered: 1) PKCe transgenic mice, treated either with TPA or UVR, elicited constitutive phosphorylation of Stat3 at both the tyrosine 705 and serine 727 residues as compared with wild-type mice. Constitutive phosphorylation of Stat3 accompanied increased expression of Stat3-regulated genes (c-myc, cyclin D1, cdc25A, and COX-2), 2) PKC? interacts with Stat3, phosphorylated serine 727 and 3) PKCe interaction with Stat3 was PKCe isoform specific and was dependent on both TPA and UVR treatment (13).
Stat3 is activated by phosphorylation of a conserved tyrosine 705, which enables dimerization, nuclear translocation, and DNA binding (15-17). However, for maximum transcriptional activity, Stat3 also requires phosphorylation of Ser727 and recruitment of transcriptional co-activators (16, 18-21). However, it is unclear to what extent such interactions of PKCe with Stat3 are of importance for optimal Stat3 transactivation and carcinogenicity and these investigations form the focus of this proposal. We hypothesize that: 1) PKCe directly and/or indirectly interacts with Stat3 to phosphorylate Stat3Ser727 and regulates its transcriptional activity. 2) PKCe-Stat3 interaction and subsequent Stat3Ser727 phosphorylation are important components of TPA and UVR signal transduction pathways to carcinogenesis. We propose the following specific aims to test these hypotheses using both intact mouse skin in vivo and mouse epidermal JB6 cells (Clone 41-5a, p+).
Specific Aim 1: To determine whether PKCe directly and/ or indirectly interacts with Stat3. Complimentary experiments, which may provide clues of PKCe-Stat3 direct interaction, will include binding of purified recombinant PKCe to Stat3. Clues about indirect interaction: GST pull-down assay to determine interaction with other kinases following transfection with GST-PKCe or GST-Stat3.
Specific Aim 2: To determine whether PKCe mediated Stat3ser727 phosphorylation regulates Stat3 nuclear translocation, Stat3 DNA binding and transcriptional activity. To accomplish this specific aim we will use JB6 cells. We will silence PKCe using specific siRNA. We will determine whether inhibition of Stat3ser727 phosphorylation inhibits Stat3 DNA-binding and transcriptional activity.
Specific Aim 3: To determine whether agents which inhibit PKCe activation and subsequent Stat3Ser727 phosphorylation inhibit JB-6 cell transformation. We will screen small molecule NIH libraries for identification of novel agents, which may inhibit PKCe activation. The JB6 cell model will then be used to determine if these agents inhibit carcinogenesis.
Publications
Aziz MH, Manoharan HT, Sand JM, Verma AK,. Protein kinase Cepsilon interacts with Stat3 and regulates its activation that is essential for the development of skin cancer. Mol Carcinog. 2007 Aug;46(8):646-53.
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