Accelerated wound healing by mTOR activation in genetically defined mouse models

The management of slow or non-healing ulcerations constitutes an increasing clinical challenge in the developed world because of the ageing of the population and the pandemic rise in type II diabetes. Recent studies suggest that molecular circuitries deployed by tumor cells to promote cancerous grow...

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Bibliographic Details
Published in:PloS one 2010-05, Vol.5 (5), p.e10643
Main Authors: Squarize, Cristiane H, Castilho, Rogerio M, Bugge, Thomas H, Gutkind, J Silvio
Format: Article
Language:English
Subjects:
1-Phosphatidylinositol 3-kinase
Aberration
Activation
AKT protein
Animal models
Animals
Cell Biology/Cell Growth and Division
Cell Biology/Cell Signaling
Cell Compartmentation - drug effects
Cell growth
Cell Movement - drug effects
Cell proliferation
Chromosomes
Dentistry
Diabetes mellitus
Enzyme Activation - drug effects
Epidemics
Epithelial cells
Epithelial Cells - drug effects
Epithelial Cells - enzymology
Epithelial Cells - pathology
Gene amplification
Gene Deletion
Intracellular Signaling Peptides and Proteins - metabolism
Keratinocytes - drug effects
Keratinocytes - enzymology
Keratinocytes - pathology
Kinases
Medicine
Mice
Models, Animal
Mutation
Pandemics
Pathology/Surgical Pathology
Pharmacology
Phosphatase
Physiology/Cell Signaling
Protein-Serine-Threonine Kinases - metabolism
Proto-Oncogene Proteins c-akt - metabolism
PTEN Phosphohydrolase - deficiency
PTEN Phosphohydrolase - metabolism
PTEN protein
Rapamycin
Regeneration
Rodents
Signal Transduction - drug effects
Signaling
Sirolimus - pharmacology
Skin
Skin - drug effects
Skin - pathology
Stem cells
Throat cancer
Tissue engineering
TOR protein
TOR Serine-Threonine Kinases
Tuberous Sclerosis Complex 1
Tumor cells
Tumor Suppressor Proteins - metabolism
Up-Regulation - drug effects
Wound care
Wound healing
Wound Healing - drug effects
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Summary:The management of slow or non-healing ulcerations constitutes an increasing clinical challenge in the developed world because of the ageing of the population and the pandemic rise in type II diabetes. Recent studies suggest that molecular circuitries deployed by tumor cells to promote cancerous growth may also contribute to tissue regeneration. Here, we exploited this emerging information to search for novel molecular targets to accelerate wound healing. We found that the activation of the PI3K-Akt-mTOR pathway, whose aberrant function is a frequent event in human neoplasia, represents an integral component of the normal wound healing process. By the use of genetically defined approaches, including the epithelial-specific ablation of Pten and Tsc1, we show that mTOR activation can dramatically increase epithelial cell proliferation, migration, and cutaneous wound healing, while pharmacological inhibition of mTOR with rapamycin delays wound closure. Overall, our findings indicate that the transient pharmacologic activation of the PI3K-Akt-mTOR signaling axis may represent a novel clinical intervention strategy to accelerate the healing of debilitating and life-threatening wounds.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0010643