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.
Highlights
The CYLD gene [1, 2] encodes an enzyme (CYLD) that is ubiquitously expressed and contains a deubiquitinating (DUB) domain at the C-terminus, which removes lysine-63 linked polyubiquitin chains.The first function described for CYLD was the inhibition of the nuclear factor (NF)-κB pathway [1], and mutations that inactivate the carboxyl-terminal deubiquitinating domain of CYLD deregulate the NF-κB activity, leading to the development of skin appendages tumors in patients of familial cylindromatosis [2].The ubiquitous NF-κB family of transcription factors is composed of dimers of five members, being the predominant dimer in skin p65/p50 [3]
We have generated a new model of transgenic mice, the K5-CYLDC/S mice, carrying the mutant CYLDC/S construct [6, 9, 23] under the regulatory elements of the keratin 5 (K5). These mice express a mutant CYLDC/S protein defective in its DUB function in the skin and other numerous organs, and our results show that they exhibit signs of accelerated aging from very early ages; they exhibit inflammation and develop spontaneous tumors in many organs
We have generated a new model of transgenic mice, the K5-CYLDC/S mice, carrying the mutant CYLDC/S construct [6] under the control of the keratin 5 (K5) promoter
Summary
The CYLD gene [1, 2] encodes an enzyme (CYLD) that is ubiquitously expressed and contains a deubiquitinating (DUB) domain at the C-terminus, which removes lysine-63 linked polyubiquitin chains.The first function described for CYLD was the inhibition of the nuclear factor (NF)-κB pathway [1], and mutations that inactivate the carboxyl-terminal deubiquitinating domain of CYLD deregulate the NF-κB activity, leading to the development of skin appendages tumors in patients of familial cylindromatosis [2].The ubiquitous NF-κB family of transcription factors is composed of dimers of five members, being the predominant dimer in skin p65/p50 [3]. The first function described for CYLD was the inhibition of the nuclear factor (NF)-κB pathway [1], and mutations that inactivate the carboxyl-terminal deubiquitinating domain of CYLD deregulate the NF-κB activity, leading to the development of skin appendages tumors in patients of familial cylindromatosis [2]. Loss of homeostasis of the epidermis and skin appendages leads to numerous skin alterations, such as alopecia, inflammatory diseases and non-melanoma skin cancer (NMSC). Our group and others have described that CYLD acts as a suppressor of the development and progression of the most aggressive form of the NMSC, i.e. skin squamous cell carcinomas (SCC) [6,7,8,9]. The role that CYLD plays in vivo in the epidermis and HF homeostasis has not been fully characterized
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