title: KIND1 Loss Sensitizes Keratinocytes to UV-Induced Inflammatory Response and DNA Damage.
abstract: Loss of function of KIND1, a cytoskeletal protein involved in β1-integrin function, causes Kindler syndrome, a genetic disease characterized by skin fragility, photosensitivity, and increased risk of squamous cell carcinoma. Dysregulation of β1-integrin underlies Kindler syndrome skin fragility. However, the mechanisms underlying squamous cell carcinoma susceptibility are unclear. Here, we demonstrate that gene silencing of KIND1 decreased keratinocyte proliferation and increased apoptosis in vitro and in skin grafts regenerated on mice, which was correlated with reduced cyclinB1. In addition, KIND1 loss sensitized keratinocytes to cytokine and UV-induced NF-κB and c-Jun N-terminal kinase activation and upregulation of CXCL10 and tumor necrosis factor-α. Moreover, KIND1 loss impaired DNA repair, as indicated by the increased detection of γH2AX and cyclobutane pyrimidine dimers 24 hours after UVB radiation. Genetic or pharmacological c-Jun N-terminal kinase inhibition and NF-κB inhibition markedly reduced cyclobutane pyrimidine dimers-positive cells. Further, we show that KIND1 was regulated by JunB at the transcriptional level and, like JunB, it was downregulated in human squamous cell carcinoma cells. Together, these results indicate that KIND1 is important not only for keratinocyte proliferation but also for the suppression of UV-induced inflammation and DNA damage. These latter findings support a tumor suppressor function for KIND1, and identify c-Jun N-terminal kinase and NF-κB as potential therapeutic targets for prevention of squamous cell carcinoma in patients with Kindler syndrome.
authors.affiliation: Department of Dermatology, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Dermatology, Duke University Medical Center, Durham, North Carolina, USA; Department of Dermatology, Tianjin Medical University General Hospital, Tianjin, PR China.
authors.forename: Suju
authors.initials: S
authors.lastname: Luo
authors.affiliation: Department of Dermatology, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Dermatology, Duke University Medical Center, Durham, North Carolina, USA; Department of Dermatology, Peking University Third Hospital, Beijing, PR China.
authors.forename: Long
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Dermatology, Duke University Medical Center, Durham, North Carolina, USA; Department of Interventional Radiology and Vascular Surgery, Peking University Third Hospital, Beijing, PR China.
authors.forename: Wen-Hui
authors.initials: WH
authors.lastname: Wang
authors.affiliation: Department of Dermatology, Duke University Medical Center, Durham, North Carolina, USA; Center of Molecular and Biomolecular Imaging, Duke University, Durham, North Carolina, USA.
authors.forename: Simone
authors.initials: S
authors.lastname: Degan
authors.affiliation: Department of Surgery, Division of Plastic, Reconstructive, Maxillofacial and Oral Surgery, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Detlev
authors.initials: D
authors.lastname: Erdmann
authors.affiliation: Department of Dermatology, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Russell
authors.initials: R
authors.lastname: Hall
authors.affiliation: Department of Dermatology, Duke University Medical Center, Durham, North Carolina, USA. Electronic address: Jennifer.zhang@duke.edu.
authors.forename: Jennifer Y
authors.initials: JY
authors.lastname: Zhang
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000209:etiology; D049109:Cell Proliferation; D002478:Cells, Cultured; D004249:DNA Damage; D006801:Humans; D007249:Inflammation / Q000209:etiology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000502:physiology; D015603:Keratinocytes / Q000528:radiation effects*; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000502:physiology; D009363:Neoplasm Proteins / Q000502:physiology*; D011740:Pyrimidine Dimers / Q000032:analysis; D014466:Ultraviolet Rays / Q000009:adverse effects*
chemical_list: C475301:FERMT1 protein, human; D008565:Membrane Proteins; D016328:NF-kappa B; D009363:Neoplasm Proteins; D011740:Pyrimidine Dimers; D048031:JNK Mitogen-Activated Protein Kinases