Keratins are abundant proteins in epithelial cells, in which they occur as a cytoplasmic network of 10-12nm wide intermediate filaments (IPs). They are encoded by a large family of conserved genes in mammals,with >50 individual members partitioned into two sequence types. A strict requirement for the heteropolymer- ization of type I and type II keratin proteins during filament assembly underlies the pain/visetranscriptional regulation of keratin genes. In addition, individual pairs are regulated in a tissue-type and differentiation- specific manner. Elucidating the rationale behind the diversity and differential distribution of keratin proteins offers the promise of novel insight into epithelial biology, in health and disease. Keratin IPs act as resilient yet pliable scaffolds that endow epithelial cells with the ability to sustain mechanical and non-mechanical stresses. Inherited mutations altering the coding sequence of keratins underlie several epithelial fragility conditions. In addition, keratin IPs modulate the cell's response to specific pro-apoptotic signals, control of cell and tissue growth, and the routing of membrane proteins in simple epithelia. Now it its ninth year, this project is centered around keratins 16 and 17, which are constitutively expressed in all epithelial appendages and induced whenever skin tissue is subjected to injury, UV exposure, and other challenges, as well as in diseases such as psoriasis and skin carcinoma. During the next period we will focus on the non-mechanical functions of K14-, K16-and K17-containing filaments in skin epithelia, with a particular emphasis on epithelial cell survival (Aim1), control of epithelial cell growth through regulation of protein synthesis (Aim 2), and the characterizationof their regulation in vivo (Aim 3). The proposal draws substantially from the consequences associatedwith lack of keratin 17 in mouse, which results in hair cycling defects secondaryto the untimely apoptosis of hair matrix epithelial cells, and in embryonic wound closure defects correlatingwith smaller size of activated epithelial cell at the wound edge. Because the K17 null phenotype is mitigated by the presence of keratin16 and the newly discovered keratin17n, we will also produce a mouse strain enabling the temporally- and spatially-controlled inactivation of the K7n-K17-K16 gene cluster (aim 4). As such, the project will further our understanding of keratin properties and function in health and indisease.
| Jacob, Justin T; Coulombe, Pierre A; Kwan, Raymond et al. (2018) Types I and II Keratin Intermediate Filaments. Cold Spring Harb Perspect Biol 10: |
| Wang, Fengrong; Chen, Song; Liu, Hans B et al. (2018) Keratin 6 regulates collective keratinocyte migration by altering cell-cell and cell-matrix adhesion. J Cell Biol 217:4314-4330 |
| Zieman, Abigail; Coulombe, Pierre A (2018) The keratin 16 null phenotype is modestly impacted by genetic strain background in mice. Exp Dermatol 27:672-674 |
| Kerns, Michelle L; Hakim, Jill M C; Zieman, Abigail et al. (2018) Sexual Dimorphism in Response to an NRF2 Inducer in a Model for Pachyonychia Congenita. J Invest Dermatol 138:1094-1100 |
| 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 |
| 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 |
| 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 |
| 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 |
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