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KIND1 Loss Sensitizes Keratinocytes to UV-Induced Inflammatory Response and DNA Damage.

Publication ,  Journal Article
Zhang, X; Luo, S; Wu, J; Zhang, L; Wang, W-H; Degan, S; Erdmann, D; Hall, R; Zhang, JY
Published in: J Invest Dermatol
February 2017

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.

Duke Scholars

Published In

J Invest Dermatol

DOI

EISSN

1523-1747

Publication Date

February 2017

Volume

137

Issue

2

Start / End Page

475 / 483

Location

United States

Related Subject Headings

  • Ultraviolet Rays
  • Pyrimidine Dimers
  • Neoplasm Proteins
  • NF-kappa B
  • Mice
  • Membrane Proteins
  • Keratinocytes
  • JNK Mitogen-Activated Protein Kinases
  • Inflammation
  • Humans
 

Citation

APA
Chicago
ICMJE
MLA
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Zhang, X., Luo, S., Wu, J., Zhang, L., Wang, W.-H., Degan, S., … Zhang, J. Y. (2017). KIND1 Loss Sensitizes Keratinocytes to UV-Induced Inflammatory Response and DNA Damage. J Invest Dermatol, 137(2), 475–483. https://doi.org/10.1016/j.jid.2016.09.023
Zhang, Xiaoling, Suju Luo, Joseph Wu, Long Zhang, Wen-Hui Wang, Simone Degan, Detlev Erdmann, Russell Hall, and Jennifer Y. Zhang. “KIND1 Loss Sensitizes Keratinocytes to UV-Induced Inflammatory Response and DNA Damage.J Invest Dermatol 137, no. 2 (February 2017): 475–83. https://doi.org/10.1016/j.jid.2016.09.023.
Zhang X, Luo S, Wu J, Zhang L, Wang W-H, Degan S, et al. KIND1 Loss Sensitizes Keratinocytes to UV-Induced Inflammatory Response and DNA Damage. J Invest Dermatol. 2017 Feb;137(2):475–83.
Zhang, Xiaoling, et al. “KIND1 Loss Sensitizes Keratinocytes to UV-Induced Inflammatory Response and DNA Damage.J Invest Dermatol, vol. 137, no. 2, Feb. 2017, pp. 475–83. Pubmed, doi:10.1016/j.jid.2016.09.023.
Zhang X, Luo S, Wu J, Zhang L, Wang W-H, Degan S, Erdmann D, Hall R, Zhang JY. KIND1 Loss Sensitizes Keratinocytes to UV-Induced Inflammatory Response and DNA Damage. J Invest Dermatol. 2017 Feb;137(2):475–483.
Journal cover image

Published In

J Invest Dermatol

DOI

EISSN

1523-1747

Publication Date

February 2017

Volume

137

Issue

2

Start / End Page

475 / 483

Location

United States

Related Subject Headings

  • Ultraviolet Rays
  • Pyrimidine Dimers
  • Neoplasm Proteins
  • NF-kappa B
  • Mice
  • Membrane Proteins
  • Keratinocytes
  • JNK Mitogen-Activated Protein Kinases
  • Inflammation
  • Humans