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Transcriptional regulation of ataxia–telangiectasia and Rad3-related protein by activated p21-activated kinase-1 protects keratinocytes in UV-B-induced premalignant skin lesions

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Abstract

Sun-induced skin lesions, in particular actinic keratosis, are generally considered as premalignant skin lesions that can progress into squamous cell carcinoma (SCC) and invasive SCC if left untreated. Therefore, understanding the molecular mechanisms by which the ultraviolet-B (UV-B)-exposed cells are being protected and the signaling pathways that promote the progression of certain premalignant skin lesions to malignant lesions will permit us to prevent or cure skin cancers. In the current study, we found that phospho-p21-activated kinase-1 (Pak1) and Pak1 expression was high in clinical samples of sunlight-induced premalignant skin lesions assessed by immunohistochemistry. Further, we observed that phospho-Pak1 and Pak1 levels are high in UV-B-exposed hairless SKH mouse model skin samples as compared with unexposed skin tissue. Our results from cell line and animal models showed that Pak1 is activated in response to UV-B radiation, and this activated Pak1 translocates from the cytoplasm to the nucleus. Inside the nucleus, Pak1 via C-Fos binds to a specific promoter region of DNA repair kinase ATR (ataxia–telangiectasia and Rad3-related protein) and acts as a transcriptional regulator of ATR. Results from our analysis showed that Pak1 overexpression, knockdown and Pak1 knockout cell line models showed that Pak1 confers protection to keratinocytes from UV-B-induced apoptosis and DNA damage via ATR. To our knowledge, this is the first study that evaluates the functional and clinical significance of a signaling molecule, Pak1, in sun-induced premalignant skin lesions and indicates that increased Pak1 activation and expression could serve as an early warning sign of progression toward non-melanoma skin cancer, if ignored.

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Acknowledgements

We thank Dr Barathidasan, Veterinary Pathologist from Mahatma Gandhi Medical College and Research Institute (MGMCRI), Pondicherry for scoring the mice slides. We also thank Rahul and Venu for help with IHC and animal studies. We thank DRDO-LSRB, Government of India, for the financial support to SKR (Grant No: DLS/81/48222/XXIII/LSRB/2009), and NCI R01CA133629 (to TMO) and Indian Institute of Technology Madras (IITM) for all other facilities.

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Authors and Affiliations

  1. Department of Biotechnology, Indian Institute of Technology Madras (IITM), Chennai, Adyar, India

    S Beesetti, J Mavuluri, R P Surabhi & S K Rayala

  2. Department of Pathology, College of Medicine, The Ohio State University, Columbus, OH, USA

    T M Oberyszyn & K Tober

  3. Department of Community Medicine, Sri Ramachandra University, Chennai, Porur, India

    R S Pitani

  4. Department of Pathology, Sri Ramachandra University, Chennai, Porur, India

    L D Joseph

  5. Department of Human Genetics, Sri Ramachandra University, Chennai, Porur, India

    G Venkatraman

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  1. S Beesetti
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Correspondence to G Venkatraman or S K Rayala.

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Beesetti, S., Mavuluri, J., Surabhi, R. et al. Transcriptional regulation of ataxia–telangiectasia and Rad3-related protein by activated p21-activated kinase-1 protects keratinocytes in UV-B-induced premalignant skin lesions. Oncogene 36, 6154–6163 (2017). https://doi.org/10.1038/onc.2017.218

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