Additional Research Interests

The making and maintenance of skin epithelia represents an excellent paradigm to understand how groups of cells acquire relevant characteristics and cooperate with one another to form a functional tissue. Historically, our approach to this important topic in biology and medicine has consisted of defining the relationship between the keratin multigene family and the architecture and function of skin epithelia. Keratins are the major structural proteins in epithelial cells, where they occur as a cytoplasmic network of 10-12 nm intermediate filaments (IFs). A large group (> 50) of type I and II keratin genes occur in mammalian genomes. Keratin genes are regulated in an epithelial tissue-type and differentiation-related fashion.

A major function of keratin filaments is to endow epithelial cells and tissues with the ability to withstand mechanical stress. Mutations affecting keratin sequences underlie several inherited blistering diseases in which epithelial cells are fragile and rupture readily upon exposure to stress. We are using biochemical and biophysical tools to determine how mutations affect the ability of keratin filaments to function in a structural capacity. A novel, recently identified function for specific keratins is to afford cellular “protection” against specific apoptosis-triggering signals (e.g., Fas, TNFa). We discovered that in skin, this function impacts on progression of hair follicles through their growth cycle, a clinically relevant and otherwise interesting phenomenon that involves the cyclic activation of resident stem cells.

Through the identification of keratin binding proteins (e.g., Akt; 14-3-3s; EF1g) and the study of various transgenic mouse models produced in the laboratory, we are also investigating potential novel functions fulfilled by various keratins in skin tissue. Altogether, these efforts are providing novel insights into fundamental aspects of skin biology in health and disease.

We have also recently taken an interest in defining the function of lamins in the skin. Lamins are nuclear-specific IF proteins forming the nuclear envelope. Mutations in lamin A/C give rise to as many as eight distinct diseases, including premature aging. We are also working to identify and characterize basic determinants responsible for the formation and growth of basal cell carcinoma in skin. BCCs usually arise from UV-induced mutations in p53 and sonic hedgehog signaling effectors represent the most frequent human cancer. These types of studies are made possible in part though our development of a system for conditional gene manipulation in mouse skin.

SELECTED PUBLICATIONS

Ma L, Yamada S, Wirtz D, Coulombe PA (2001). A “Hot-Spot” Mutation Alters the Mechanical Properties of Keratin Filament Networks. Nat.. Cell Biol. 3:503-506.

McGowan KM, Tong X, Colucci-Guyon E, Langa F, Babinet C, Coulombe PA (2002). Keratin 17 null mice exhibit age- and strain-dependent alopecia. Genes & Dev. 16:1412-22.

Mazzalupo S, Wawersik MJ, Coulombe PA (2002). An ex vivo assay to assess the potential of skin keratinocytes for wound epithelialization. J. Invest. Dermatol. 118: 866-70.

Wong P, Coulombe PA (2003). Loss of keratin 6 (K6) proteins reveals a function for intermediate filaments during wound repair. J. Cell Biol. 163: 327-37.

Tong X, Coulombe PA (2003). Mouse models for Alopecia: Structural genes that are baldly needed. Trends Mol. Med. 9: 79-84.

Zarach JM, Beaudoin III GM, Coulombe PA, Thompson CC (2004). The co-repressor hairless has a role in epithelial cell differentiation in the skin. Development 131:4189-200.

Coulombe PA, Wong P (2004). Cytoplasmic intermediate filaments revealed as dynamic and multipurpose scaffolds. Nat Cell Biol. 6:699-706.

Omary MB, Coulombe PA, McLean WH (2004). Intermediate filament proteins and their associated diseases. New Engl. J. Med. In press for Nov. 11 issue.




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