p53 Is a Direct Transcriptional Repressor of Keratin 17: Lessons from a Rat Model of Radiation Dermatitis

Abstract

The intermediate filament protein keratin 17 (Krt17) shows highly dynamic and inducible expression in skin physiology and pathology. Because Krt17 exerts physiologically important functions beyond providing structural stability to keratinocytes whereas abnormal Krt17 expression is a key feature of dermatoses such as psoriasis and pachyonychia congenita, the currently unclear regulation of Krt17 expression needs to be better understood. Using a rat model of radiation dermatitis, we report here that Krt17 expression initially is down-regulated but later is strongly up-regulated by ionizing radiation. The early down-regulation correlates with the activation of p53 signaling. Deletion of p53 abolishes the initial down-regulation but not its subsequent up-regulation, suggesting that p53 represses Krt17 transcription. Because previous work reported up-regulation of Krt17 by ultraviolet irradiation, which also activates p53 signaling, the effect of ultraviolet radiation was reexamined. This revealed that the initial down-regulation of Krt17 is conserved, but the up-regulation comes much faster. Chromatin immunoprecipitation analysis in vivo and electromobility shift assay in vitro identified two p53-binding sites in the promoter region of Krt17. Thus, p53 operates as a direct Krt17 repressor, which invites therapeutic targeting in dermatoses characterized by excessive Krt17 expression.

Keratin 17 in disease pathogenesis: from cancer to dermatoses

“…In radiation dermatitis, p53 repressed K17 transcription and K17 expression showed an inverse correlation with p53 activation in a mouse model. Mapping the promoter region of Krt17 revealed two putative p53 binding sites . This p53–K17 negative regulatory mechanism raises the possibility of employing p53 for the treatment of K17‐related dermatoses.…”

Genome-wide analysis suggests a differential microRNA signature associated with normal and diabetic human corneal limbus

“…This may involve fine-tuned regulation of proliferation to the exact need of the tissue by miR-10b through its downregulation of DKK1 and GSK-3β, which leads to upregulation of Wnt signaling 24, 57, 60 . Further, miR-10b indirectly regulates LESC/TA cell K17, which may be through direct targeting of p53 63 . Eventually, the committed cells differentiate while migrating laterally and upward out of the reach of Wnt signaling and under PAX6 and KLF4 regulatory mechanisms for terminal differentiation 29–31, 40, 42 .…”

How chemotherapy and radiotherapy damage the tissue: Comparative biology lessons from feather and hair models

“…Generally, mammalian skin is much more radio‐resistant than its appendages. Only after a higher dose of 40 Gy irradiation, a significant damage to the murine skin epidermis is induced in a process termed “radiation dermatitis.” For IR‐induced epidermal damage, a recently revealed key event is the disruption of adherens junctions, which then leads to loss of cell‐cell contact between epidermal keratinocytes. In rodent epidermis, this disruption of cell adhesion is mediated by ROS‐activated Src/Abl kinases and subsequent degradation of the E‐cadherin/β‐catenin complex; activation of Wnt and Hippo signalling are then followed to drive skin regeneration .…”

“…In rodent epidermis, this disruption of cell adhesion is mediated by ROS‐activated Src/Abl kinases and subsequent degradation of the E‐cadherin/β‐catenin complex; activation of Wnt and Hippo signalling are then followed to drive skin regeneration . Interestingly, the epidermal keratinocytes do not undergo apoptosis even after 40 Gy IR irradiation; rather, they enter a mitotic catastrophe programme and are replaced by clonal expansion from residual epidermal stem cells …”