Multiple outcomes of the germline p16 INK4a mutation affecting senescence and immunity in human skin.

Autor: Subramanian P; Division of Medicine, University College London, London, UK., Sayegh S; Division of Medicine, University College London, London, UK., Laphanuwat P; Division of Medicine, University College London, London, UK.; Department of Pharmacology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand., Devine OP; Division of Medicine, University College London, London, UK., Fantecelle CH; Núcleo de Doenças Infecciosas, Universidade Federal Do Espírito Santo, Vitória, Brazil., Sikora J; Centre for Immunobiology, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK., Chambers ES; Centre for Immunobiology, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK., Karagiannis SN; St. John's Institute for Dermatology, School of Basic and Medical Biosciences, King's College London, Guy's Hospital, London, UK.; Breast Cancer Now Research Unit, School of Cancer & Pharmaceutical Sciences, Guy's Cancer Centre, King's College London, London, UK., Gomes DCO; Núcleo de Doenças Infecciosas, Universidade Federal Do Espírito Santo, Vitória, Brazil., Kulkarni A; Clinical Genetics Department, Guys and St. Thomas' NHS Foundation Trust, London, UK., Rustin MHA; Department of Dermatology, Royal Free Hospital, London, UK., Lacy KE; St. John's Institute for Dermatology, School of Basic and Medical Biosciences, King's College London, Guy's Hospital, London, UK., Akbar AN; Division of Medicine, University College London, London, UK.
Jazyk: angličtina
Zdroj: Aging cell [Aging Cell] 2024 Oct 17, pp. e14373. Date of Electronic Publication: 2024 Oct 17.
DOI: 10.1111/acel.14373
Abstrakt: The integrated behaviour of multiple senescent cell types within a single human tissue leading to the development of malignancy is unclear. Patients with Familial Melanoma Syndrome (FMS) have heterozygous germline defects in the CDKN2A gene coding for the cyclin inhibitor p16 INK4a . Melanocytes within skin biopsies from FMS patients express significantly less p16 INK4a but express higher levels of the DNA-damage protein 𝛾H2AX a than fibroblastic cells. However, patient fibroblasts also exhibit defects since senescent cells do not increase in the skin during ageing and fibroblasts isolated from the skin of patients have increased replicative capacity compared to control fibroblasts in vitro, culminating in abnormal nuclear morphology. Patient derived fibroblasts also secreted less SASP than control cells. Predisposition of FMS patients to melanoma may therefore result from integrated dysregulation of senescence in multiple cell types in vivo. The inherently greater levels of DNA damage and the overdependence of melanocytes on p16 for cell cycle inhibition after DNA damage makes them exquisitely susceptible to malignant transformation. This may be accentuated by senescence-related defects in fibroblasts, in particular reduced SASP secretion that hinders recruitment of T cells in the steady state and thus reduces cutaneous immunosurveillance in vivo.
(© 2024 The Author(s). Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)
Databáze: MEDLINE
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