Type I and type II keratin genes and their proteins undergo a tight regulation in a tissue-specific, differentiation-related, and context-dependent fashion in epithelial cells. Most disease states, including cancer, involve a departure from normal physiology and are invariably accompanied by aberrations in cellular differentiation pathways and keratin regulation. In addition to a ubiquitous and critically important role of structural support, keratin proteins were recently found to impact several key signaling pathways in epithelia. Two recent studies point to a significant modulatory role for two partner keratin proteins, keratin 17 and keratin 5, in basal cell carcinoma and related basaloid skin tumors. This project aims at defining the mechanistic link between these keratins and tumorigenesis in skin, and explore whether it applies to other epithelial tissues.
Our specific aims for this project will be as follows.
In Aim 1, we will seek to define the molecular mechanism(s) through which keratin 17 enhances the expression of select cytokines and chemokines in Gli2-overexpressing, tumor-prone skin keratinocytes.
In Aim 2, we will seek to define the mechanism(s) through which two variants in keratin 5 (Gly138Glu and Asp197Glu) enhance the risk of developing basal cell carcinoma.
In Aim 3, we will explore whether keratin 17 impacts the skin and cervical tumors arising in transgenic mice constitutively expressing the E6 and E7 oncoproteins from human papillomavirus 16, and then investigate whether the mechanism(s) underlying keratin-dependent modulation of tumor growth are the same as those uncovered in basal cell carcinoma and basaloid skin tumors. The mechanistic insight acquired about novel determinants of tumor cell architecture and regulation may lead to the identification of new therapeutic targets in the fight against cancer.

Public Health Relevance

Keratins, the major intermediate filament-forming proteins occurring in epithelia, undergo tight regulation in a tissue-specific, differentiation-related, and context-dependent fashion;accordingly, alterations in keratin expression are useful clinically to typify the cellular origin of cancers and diagnose tumor stage. Two very recent studies implicate keratin proteins in the risk towards, and growth properties of, basal cell carcinoma and related basaloid skin tumors in the human and in a transgenic mouse model. This project builds upon these efforts and seeks to understand the cellular and molecular mechanistic basis of the impact of select keratin proteins on the properties of tumors.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA160255-01
Application #
8153731
Study Section
Molecular Oncogenesis Study Section (MONC)
Program Officer
Okano, Paul
Project Start
2011-07-01
Project End
2016-04-30
Budget Start
2011-07-01
Budget End
2012-04-30
Support Year
1
Fiscal Year
2011
Total Cost
$374,560
Indirect Cost
Name
Johns Hopkins University
Department
Biochemistry
Type
Schools of Public Health
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Coulombe, Pierre A (2017) The Molecular Revolution in Cutaneous Biology: Keratin Genes and their Associated Disease: Diversity, Opportunities, and Challenges. J Invest Dermatol 137:e67-e71
Hobbs, Ryan P; Jacob, Justin T; Coulombe, Pierre A (2016) Keratins Are Going Nuclear. Dev Cell 38:227-33
Kerns, Michelle L; Hakim, Jill M C; Lu, Rosemary G et al. (2016) Oxidative stress and dysfunctional NRF2 underlie pachyonychia congenita phenotypes. J Clin Invest 126:2356-66
Hobbs, R P; Batazzi, A S; Han, M C et al. (2016) Loss of Keratin 17 induces tissue-specific cytokine polarization and cellular differentiation in HPV16-driven cervical tumorigenesis in vivo. Oncogene 35:5653-5662
Wang, Fengrong; Zieman, Abigail; Coulombe, Pierre A (2016) Skin Keratins. Methods Enzymol 568:303-50
Hobbs, Ryan P; DePianto, Daryle J; Jacob, Justin T et al. (2015) Keratin-dependent regulation of Aire and gene expression in skin tumor keratinocytes. Nat Genet 47:933-8
Chung, Byung Min; Arutyunov, Artem; Ilagan, Erika et al. (2015) Regulation of C-X-C chemokine gene expression by keratin 17 and hnRNP K in skin tumor keratinocytes. J Cell Biol 208:613-27
Chung, Byung-Min; Rotty, Jeremy D; Coulombe, Pierre A (2013) Networking galore: intermediate filaments and cell migration. Curr Opin Cell Biol 25:600-12
Pan, Xiaoou; Hobbs, Ryan P; Coulombe, Pierre A (2013) The expanding significance of keratin intermediate filaments in normal and diseased epithelia. Curr Opin Cell Biol 25:47-56
Coulombe, Pierre A; Lee, Chang-Hun (2012) Defining keratin protein function in skin epithelia: epidermolysis bullosa simplex and its aftermath. J Invest Dermatol 132:763-75

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