The anti-apoptotic role of PPARbeta contributes to efficient skin wound healing.
PPARalpha and PPARbeta are expressed in the mouse epidermis during fetal development, but their expression progressively disappears after birth. However, the expression of PPARbeta is reactivated in adult mice upon proliferative stimuli, such as cutaneous injury. We show here that PPARbeta protects keratinocytes from growth factor deprivation, anoikis and TNF-alpha-induced apoptosis, by modulating both early and late apoptotic events via the Akt1 signaling pathway and DNA fragmentation, respectively. The control mechanisms involve direct transcriptional upregulation of ILK, PDK1, and ICAD-L. In accordance with the anti-apoptotic role of PPARbeta observed in vitro, the balance between proliferation and apoptosis is altered in the epidermis of wounded PPARbeta mutant mice, with increased keratinocyte proliferation and apoptosis. In addition, primary keratinocytes deleted for PPARbeta show defects in both cell-matrix and cell-cell contacts, and impaired cell migration. Together, these results suggest that the delayed wound closure observed in PPARbeta mutant mice involves the alteration of several key processes. Finally, comparison of PPARbeta and Akt1 knock-out mice reveals many similarities, and suggests that the ability of PPARbeta to modulate the Akt1 pathway has significant impact during skin wound healing.
Di-Poï
Nicolas
N
Center for Integrative Genomics, NCCR Frontiers in Genetics, University of Lausanne, CH-1015 Lausanne, Switzerland.
Michalik
Liliane
L
Tan
Nguan Soon
NS
Desvergne
Béatrice
B
Wahli
Walter
W
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002460:Cell Line; D003001:Cloning, Molecular; D053938:DNA Fragmentation; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D007700:Kinetics; D051379:Mice; D018345:Mice, Knockout; D018384:Oxidative Stress / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D018160:Receptors, Cytoplasmic and Nuclear / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011994:Recombinant Proteins / Q000378:metabolism; D012879:Skin Physiological Phenomena; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014945:Wound Healing / Q000502:physiology*
D011518:Proto-Oncogene Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D011994:Recombinant Proteins; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt