The Role of p63 and the chromatin remodeler Lsh in senescence, tumor development and lymphangiogenesis
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Keyes, William M.
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214 p.
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Citation
Pecoraro, M. The Role of p63 and the chromatin remodeler Lsh in senescence, tumor development and lymphangiogenesis. Universitat Pompeu Fabra; 2014. handle: http://hdl.handle.net/10803/326749
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Doctoral program
Programa de doctorat en Biomedicina
Abstract
La senescencia celular es una detención irreversible del ciclo celular que tiene lugar en respuesta a diversos estímulos de estrés, actuando como un mecanismo supresor de tumores para impedir la proliferación de células con riesgo de transformación maligna. Así, mutaciones que interfieren con el proceso de la senescencia pueden favorecer la formación tumoral. De todas formas, cada vez hay más pruebas que sugieren que las células senescentes también pueden ejercer efectos pro-tumorigénicos en el tejido circundante mediante el fenotipo secretor asociado a senescencia (SASP). Así, descifrar los mediadores moleculares de la senescencia y el SASP es crítico para entender los estadios tempranos de la formación y progresión tumoral. Aquí mostramos que la isoforma ΔNα de p63, un factor de transcripción relacionado con p53, es un oncogén que promueve la iniciación tumoral en colaboración con Ras mediante la inhibición de la senescencia inducida por oncogenes (OIS). Efectivamente, el incremento en la expresión de ΔNp63α en queratinocitos primarios de ratón bloquea la OIS y directamente conduce a la formación de un carcinoma de células escamosas (SCC). También identificamos la Helicasa Específica Linfoide (Lsh), un miembro de la familia SNF2 de remodeladores de la cromatina, como nueva diana de p63 necesaria para la inhibición de la senescencia. Posteriormente, demostramos que Lsh es suficiente para iniciar la formación tumoral independientemente de p63, y que el aumento en su expresión conduce a un desarrollo tumoral más agresivo. Sorprendentemente, mostramos que Lsh tiene un papel en la inducción de la linfangiogénesis, un proceso característico de la progresión maligna y la metástasis. Es interesante notar que las pruebas apuntan hacia Lsh actuando sobre el SASP para dirigir la formación y la progresión tumoral. En conjunto, en este trabajo se identifican nuevos mediadores críticos de la senescencia y funciones de la desregulación de la senescencia durante la formación y la progresión tumoral.
Cellular senescence is an irreversible cell cycle arrest that occurs in response to various stresses, acting as a tumor-suppressive mechanism to impede the proliferation of cells at risk for malignant transformation. As such, mutations that interfere with the senescence process can favor tumor formation. However, increasing evidence suggests that senescent cells can also exert pro-tumorigenic effects on the surrounding tissue, through the senescence-associated secretory phenotype (SASP). As such, understanding the molecular mediators of senescence and the SASP is critical to unravel the early stages of tumor formation and progression. Here we show that the ΔNα isoform of p63, a p53-related transcription factor, is an oncogene that promotes tumor initiation in cooperation with Ras, through the inhibition of oncogene-induced senescence (OIS). Indeed, increased expression of Np63 in primary mouse keratinocytes blocks OIS and directly leads to the formation of squamous cell carcinoma (SCC). We also identify Lymphoid Specific Helicase (Lsh), a member of the SNF2 family of chromatin remodelers, as a novel target of p63, required for senescence bypass. Subsequently, we demonstrate that Lsh is sufficient to initiate tumor formation independently of p63, and that its increased expression leads to aggressive tumor development. Surprisingly, we show a role for Lsh in the induction of lymphangiogenesis, a hallmark of malignant progression and metastasis. Interestingly, the evidence points towards Lsh acting on the SASP to instruct tumor formation and progression. Together, this work identifies critical new mediators of senescence, and functional roles for senescence deregulation during tumor formation and progression.
Cellular senescence is an irreversible cell cycle arrest that occurs in response to various stresses, acting as a tumor-suppressive mechanism to impede the proliferation of cells at risk for malignant transformation. As such, mutations that interfere with the senescence process can favor tumor formation. However, increasing evidence suggests that senescent cells can also exert pro-tumorigenic effects on the surrounding tissue, through the senescence-associated secretory phenotype (SASP). As such, understanding the molecular mediators of senescence and the SASP is critical to unravel the early stages of tumor formation and progression. Here we show that the ΔNα isoform of p63, a p53-related transcription factor, is an oncogene that promotes tumor initiation in cooperation with Ras, through the inhibition of oncogene-induced senescence (OIS). Indeed, increased expression of Np63 in primary mouse keratinocytes blocks OIS and directly leads to the formation of squamous cell carcinoma (SCC). We also identify Lymphoid Specific Helicase (Lsh), a member of the SNF2 family of chromatin remodelers, as a novel target of p63, required for senescence bypass. Subsequently, we demonstrate that Lsh is sufficient to initiate tumor formation independently of p63, and that its increased expression leads to aggressive tumor development. Surprisingly, we show a role for Lsh in the induction of lymphangiogenesis, a hallmark of malignant progression and metastasis. Interestingly, the evidence points towards Lsh acting on the SASP to instruct tumor formation and progression. Together, this work identifies critical new mediators of senescence, and functional roles for senescence deregulation during tumor formation and progression.
Keywords
Angiogenesis, EMT, Fibrosarcoma, Helicase, Inflammation, Keratinocytes, Lsh, Lymphangiogenesis, Oncogene, p53, p63, SASP, Senescence, Skin, Stem cells, Helicasa, Inflamación, Queratinocitos, Linfangiogénesis, Nódulo linfático, Macrófagos, Carcinoma de células escamosas, Células madre
Subjects
576 - Cellular and subcellular biology. Cytology
Publisher
Universitat Pompeu Fabra
