Non-melanoma skin carcinogenesis; gene expression in epidermal stem cells in context of chemical and UV induced carcinogenesis.
Epidermal stem cells, posttranscriptional gene regulation, mRNA stability, RNPs, mRNA translation
Raf/MEK/ERK pathway, the polyamine pathway, mTOR-dependent pathways, ATM/ATR, NF-kB, apoptosis
Non-melanoma skin cancer (NMSC).
Focus Groups: Integumentary;
Research description: Basic/Translational
Our research focuses on the polyamine pathway and mTOR-dependent pathways in early skin cancer development. There is strong experimental evidence indicating the location of epidermal stem cells that are modified by carcinogen exposure is in the hair follicle bulge. By directing expression of transgenes to this region of the epidermis, we can modify gene expression in stem cells and ask what effect these genetic alterations have on tumor development. Using transgenic models, we were the first to show a link between induction of the Raf/MEK/ERK pathway and increased ornithine decarboxylase (ODC), the first enzyme in polyamine biosynthesis, in skin tumors. Importantly, we have established that high ODC activity is a necessary component of MEK-induced skin tumor development, and both antizyme (AZ), which binds to ODC and causes it to be degraded, and DFMO, a suicide inactivator of ODC, are a powerful suppressors of these tumors. Current work explores the role of mTOR-dependent pathways in skin carcinogenesis in response to both chemical carcinogens and UV light using mice with conditional deletion of mTOR, the mTORC1 component raptor, or the mTORC2 component rictor.
Technical expertise: chemical induction of skin cancer, skin and tumor biochemical processing and analysis, analysis of posttranscriptional regulation of gene expression: analysis of polysomal RNA integrity and polysomal association of mRNAs, mRNP assay; transgenic animal models.
- Feehan RP, Shantz LM. Molecular signaling cascades involved in nonmelanoma skin carcinogenesis. Biochem J. 2016 Oct 01; 473(19):2973-94.
- Nowotarski SL, Origanti S, Sass-Kuhn S, Shantz LM. Destabilization of the ornithine decarboxylase mRNA transcript by the RNA-binding protein tristetraprolin. Amino Acids. 2016 Oct; 48(10):2303-11.
- Nowotarski SL, Shantz LM. Cytoplasmic accumulation of the RNA-binding protein HuR stabilizes the ornithine decarboxylase transcript in a murine nonmelanoma skin cancer model. J Biol Chem. 2010 Oct 8; 285(41):31885-94.
- Shantz LM. Transcriptional and translational control of ornithine decarboxylase during Ras transformation. Biochem J. 2004 Jan 1; 377(Pt 1):257-64.