TY - JOUR
T1 - Great promises yet to be fulfilled
T2 - Defining keratin intermediate filament function in vivo
AU - Coulombe, Pierre A.
AU - Tong, Xuemei
AU - Mazzalupo, Stacy
AU - Wang, Zhiling
AU - Wong, Pauline
N1 - Funding Information:
Acknowledgements. We are very grateful to Drs. Charles Babinet and Emma Colucci (Institut Pasteur, Paris, France), Ms. Angie Lebrun (AML Laboratories, Baltimore, MD), the staff of the Microscopy and Transgenic Mouse Core Facilities at Johns Hopkins University School of Medicine, and past and present members of the Coulombe laboratory for collaboration, advice and support. This work was supported by National Institutes of Health grants AR44232 and AR42047 to P. A. Coulombe.
PY - 2004/12
Y1 - 2004/12
N2 - Keratins are abundant proteins in epithelial cells, in which they occur as a cytoplasmic network of 10-12 nm wide intermediate filaments (IFs). They are encoded by a large family of conserved genes in mammals, with more than 50 individual members partitioned into two sequence types. A strict requirement for the heteropolymerization of type I and type II keratin proteins during filament formation underlies the pairwise transcriptional 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. At present, we know that keratin IFs act as resilient yet pliable scaffolds that endow epithelial cells with the ability to sustain mechanical and non-mechanical stresses. Accordingly, inherited mutations altering the coding sequence of keratins underlie several epithelial fragility disorders. In addition, keratin IFs influence the cellular response to pro-apoptotic signals in specific settings, and the routing of membrane proteins in polarized epithelia. Here we review studies focused on a subset of keratin genes, K6, K16 and K17, showing a complex regulation in vivo, including a widely known upregulation during wound repair and in diseased skin. Progress in defining the function of these and other keratins through gene manipulation in mice has been hampered by functional redundancy within the family. Still, detailed studies of the phenotype exhibited by K6 and K17 null mice yielded novel insight into the properties and function of keratin IFs in vivo.
AB - Keratins are abundant proteins in epithelial cells, in which they occur as a cytoplasmic network of 10-12 nm wide intermediate filaments (IFs). They are encoded by a large family of conserved genes in mammals, with more than 50 individual members partitioned into two sequence types. A strict requirement for the heteropolymerization of type I and type II keratin proteins during filament formation underlies the pairwise transcriptional 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. At present, we know that keratin IFs act as resilient yet pliable scaffolds that endow epithelial cells with the ability to sustain mechanical and non-mechanical stresses. Accordingly, inherited mutations altering the coding sequence of keratins underlie several epithelial fragility disorders. In addition, keratin IFs influence the cellular response to pro-apoptotic signals in specific settings, and the routing of membrane proteins in polarized epithelia. Here we review studies focused on a subset of keratin genes, K6, K16 and K17, showing a complex regulation in vivo, including a widely known upregulation during wound repair and in diseased skin. Progress in defining the function of these and other keratins through gene manipulation in mice has been hampered by functional redundancy within the family. Still, detailed studies of the phenotype exhibited by K6 and K17 null mice yielded novel insight into the properties and function of keratin IFs in vivo.
KW - Ectodermal dysplasia
KW - Functional redundancy
KW - Hair
KW - Injury
KW - Keratins
KW - Nail
KW - Wound repair
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U2 - 10.1078/0171-9335-00443
DO - 10.1078/0171-9335-00443
M3 - Article
C2 - 15679118
AN - SCOPUS:12344276291
SN - 0171-9335
VL - 83
SP - 735
EP - 746
JO - European journal of cell biology
JF - European journal of cell biology
IS - 11-12
ER -