Publication: Implicación de CYLD en la homeostasis y tumorigénesis de piel y en el envejecimiento
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2018-09-12
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Universidad Complutense de Madrid
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Abstract
El gen Cyld fue identificado como un gen supresor tumoral mutado en lacilindromatosis familiar, enfermedad autosómica dominante que origina el desarrollode tumores derivados de anejos de la piel (cilindromas). La proteína CYLD es unaenzima que tiene en su extremo C-terminal un dominio catalítico con funcióndesubiquitinasa que elimina las cadenas de poliubiquitina en residuos de lisina-63 (laubiquitinación en este residuo está asociada a diversos procesos biológicos). Es en eldominio C-terminal de CYLD donde se han encontrado en pacientes decilindromatosis familiar la mayoría de las mutaciones, que dan lugar a una proteínacatalíticamente inactiva. CYLD regula negativamente la activación de diferentes vías,entre ellas la de los factores de transcripción NF-κB, JNK y p38MAPK.CYLD se expresa de forma ubicua prácticamente en todos los tipos celulares. Sinembargo, su inactivación en pacientes solo origina el desarrollo de tumores de losanejos de la piel, lo que sugiere que su función principal es mantener la homeostasiscutánea. Hasta ahora no se han realizado estudios encaminados a conocer cuál es elpapel de CYLD en la piel y éste es uno de nuestros objetivos principales en estetrabajo. Además, queremos analizar si CYLD puede actuar también como supresortumoral de los carcinomas escamosos cutáneos (cSCC), que son el tipo de cáncer depiel no melanoma (CPNM) más agresivo, encontrándose entre un 5 y un 15% decSCC que metastatizan. Para estos cSCC metastásicos no se ha encontrado untratamiento eficaz, y la supervivencia es muy baja, por lo que debido a la incidenciatan elevada del CPNM (es el cáncer humano más común), la mortalidad concomitantea los cSCC alcanza cifras muy elevadas. Para conseguir terapias efectivas en eltratamiento de los cSCC más agresivos es necesario encontrar biomarcadores demalignidad y nuevas dianas terapéuticas, por lo que resulta imprescindible caracterizarlos mecanismos moleculares encargados de mantener la homeostasis de la piel y deoriginar el desarrollo y progresión de los cSCC...
The Cyld gene was identified as a mutated tumor suppressor gene in familialcylindromatosis, an autosomal dominant disease that causes the development oftumors derived from skin appendages (cylindromas). The CYLD protein is an enzymecontaining a C-terminal catalytic domain with a deubiquitinase function , eliminating thepolyubiquitin chains in lysine-63 residues (the ubiquitination in this residue isassociated to diverse biological processes). In patients with familial cylindromatosis,most of the mutations have been found in the C-terminal domain of CYLD, whichresults in a catalytically inactive protein. CYLD negatively regulates the activation ofdifferent pathways, including those of the NF-κB transcription factor, JNK andp38MAPK.CYLD is ubiquitously expressed in almost all cell types. However, its inactivation inpatients causes the development of tumors derived from skin appendages, suggestingthat its main function is to maintain cutaneous homeostasis. To date, there have notbeen studies aimed to study the role that CYLD develops in the skin, which is one ofour main objectives in this work. In addition, our purpose is to analyze whether CYLDcan also act as a tumor suppressor for cutaneous squamous cell carcinoma (cSCC),as this which the most aggressive type of non-melanoma skin cancer (NMSC). cSCCexhibit a metastasis rate of 5 to 15%. It has not been found any effective treatment forthese metastatic cSCCs, and patient survival rate is very low. As a result of the highincidence of NMSC (the most common human cancer), the concomitant mortalityassociated to cSCC reaches very high levels. To achieve effective therapies in thetreatment of the cSCCs with highest risk of metastasis, it is necessary to findbiomarkers of malignancy as well as new therapeutic targets. Therefore, thecharacterization of the molecular mechanisms responsible for maintaining the skinhomeostasis is needed; it is also necessary to identify the mechanisms causing thedevelopment and progression of cSCC...
The Cyld gene was identified as a mutated tumor suppressor gene in familialcylindromatosis, an autosomal dominant disease that causes the development oftumors derived from skin appendages (cylindromas). The CYLD protein is an enzymecontaining a C-terminal catalytic domain with a deubiquitinase function , eliminating thepolyubiquitin chains in lysine-63 residues (the ubiquitination in this residue isassociated to diverse biological processes). In patients with familial cylindromatosis,most of the mutations have been found in the C-terminal domain of CYLD, whichresults in a catalytically inactive protein. CYLD negatively regulates the activation ofdifferent pathways, including those of the NF-κB transcription factor, JNK andp38MAPK.CYLD is ubiquitously expressed in almost all cell types. However, its inactivation inpatients causes the development of tumors derived from skin appendages, suggestingthat its main function is to maintain cutaneous homeostasis. To date, there have notbeen studies aimed to study the role that CYLD develops in the skin, which is one ofour main objectives in this work. In addition, our purpose is to analyze whether CYLDcan also act as a tumor suppressor for cutaneous squamous cell carcinoma (cSCC),as this which the most aggressive type of non-melanoma skin cancer (NMSC). cSCCexhibit a metastasis rate of 5 to 15%. It has not been found any effective treatment forthese metastatic cSCCs, and patient survival rate is very low. As a result of the highincidence of NMSC (the most common human cancer), the concomitant mortalityassociated to cSCC reaches very high levels. To achieve effective therapies in thetreatment of the cSCCs with highest risk of metastasis, it is necessary to findbiomarkers of malignancy as well as new therapeutic targets. Therefore, thecharacterization of the molecular mechanisms responsible for maintaining the skinhomeostasis is needed; it is also necessary to identify the mechanisms causing thedevelopment and progression of cSCC...
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Tesis de la Universidad Complutense de Madrid, Facultad de Ciencias Químicas, Departamento de Bioquímica y Biología Molecular I, leída el 22-06-2017