Research Paper Volume 11, Issue 1 pp 127—159

Premature aging and cancer development in transgenic mice lacking functional CYLD

Josefa P. Alameda 1, 2, , Ángel Ramírez 1, 2, , Rosa A. García-Fernández 3, , Manuel Navarro 1, 2, , Angustias Page 1, 2, , José C. Segovia 4, , Rebeca Sanchez 4, , Cristian Suárez-Cabrera 1, 2, , Jesús M. Paramio 1, 2, , Ana Bravo 5, , M. Jesús Fernández-Aceñero 6, , M. Llanos Casanova 1, 2, ,

  • 1 Molecular Oncology Unit, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT)/CIBERONC, Madrid 28040, Spain
  • 2 Biomedical Research Institute I+12, 12 de Octubre University Hospital, Madrid 28040, Spain
  • 3 Department of Animal Medicine and Surgery, Faculty of Veterinary, UCM, Madrid 28040, Spain
  • 4 Division of Hematopoietic Innovative Therapies, CIEMAT/CIBERER/II-FJD, Madrid 28040, Spain
  • 5 Department of Anatomy, Animal Production and Veterinary Clinical Sciences, Faculty of Veterinary Medicine, University of Santiago de Compostela, Lugo, Spain
  • 6 Servicio de Anatomía Patológica Hospital Clínico San Carlos, Departamento de Anatomía Patológica, Facultad de Medicina, UCM, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid 28040, España

received: October 9, 2018 ; accepted: December 17, 2018 ; published: January 10, 2019 ;

https://doi.org/10.18632/aging.101732
How to Cite

Copyright: Alameda et al. This is an open‐access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

CYLD is a deubiquitinating enzyme known for its role as a tumor suppressor whose mutation leads to skin appendages tumors and other cancers. In this manuscript we report that the tumor suppressor CYLD, similarly to other renowned tumor suppressor genes, protects from premature aging and cancer. We have generated transgenic mice expressing the mutant CYLDC/S protein, lacking its deubiquitinase function, under the control of the keratin 5 promoter, the K5-CYLDC/S mice. These mice express the transgene in different organs, including those considered to be more susceptible to aging, such as skin and thymus. Our results show that K5-CYLDC/S mice exhibit epidermal, hair follicle, and sebaceous gland alterations; and, importantly, they show signs of premature aging from an early age. Typically, 3-month-old K5-CYLDC/S mice exhibit a phenotype characterized by alopecia and kyphosis, and, the histological examination reveals that transgenic mice show signs of accelerated aging in numerous organs such as skin, thymus, pancreas, liver and lung. Additionally, they spontaneously develop tumors of diverse origin. Over-activation of the NF-κB pathway, along with hyperactivation of Akt, JNK and c-Myc, and chronic inflammation, appear as the mechanisms responsible for the premature aging of the K5-CYLDC/S mice.

Abbreviations

ORS: outer root sheath; HF: hair follicle; ADC: adenocarcinoma; HCC: hepatocarcinoma; SCC: squamous cell carcinoma; DUB: deubiquitinase; NMSC: non melanoma skin cancer.