mTOR mediates Wnt-induced epidermal stem cell exhaustion and aging.
Epidermal integrity is a complex process established during embryogenesis and maintained throughout the organism lifespan by epithelial stem cells. Although Wnt regulates normal epithelial stem cell renewal, aberrant Wnt signaling can contribute to cancerous growth. Here, we explored the consequences of persistent expressing Wnt1 in an epidermal compartment that includes the epithelial stem cells. Surprisingly, Wnt caused the rapid growth of the hair follicles, but this was followed by epithelial cell senescence, disappearance of the epidermal stem cell compartment, and progressive hair loss. Although Wnt1 induced the activation of beta-catenin and the mTOR pathway, both hair follicle hyperproliferation and stem cell exhaustion were strictly dependent on mTOR function. These findings suggest that whereas activation of beta-catenin contributes to tumor growth, epithelial stem cells may be endowed with a protective mechanism that results in cell senescence upon the persistent stimulation of proliferative pathways that activate mTOR, ultimately suppressing tumor formation.
Castilho
Rogerio M
RM
Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA.
Squarize
Cristiane H
CH
Chodosh
Lewis A
LA
Williams
Bart O
BO
Gutkind
J Silvio
JS
D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002469:Cell Separation; D016922:Cellular Senescence / Q000187:drug effects; D004318:Doxycycline / Q000494:pharmacology; D000078404:Epidermal Cells; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018859:Hair Follicle / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D011494:Protein Kinases / Q000378:metabolism*; D012038:Regeneration / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology; D013234:Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism
D018952:Antigens, CD34; D051153:Wnt Proteins; D051176:beta Catenin; D011494:Protein Kinases; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D004318:Doxycycline; D020123:Sirolimus