RESUMEN

GABARAP belongs to an evolutionary highly conserved gene family that has a fundamental role in autophagy. There is ample evidence for a crosstalk between autophagy and apoptosis as well as the immune response. However, the molecular details for these interactions are not fully characterized. Here, we report that the ablation of murine GABARAP, a member of the Atg8/LC3 family that is central to autophagosome formation, suppresses the incidence of tumor formation mediated by the carcinogen DMBA and results in an enhancement of the immune response through increased secretion of IL-1ß, IL-6, IL-2 and IFN-γ from stimulated macrophages and lymphocytes. In contrast, TGF-ß1 was significantly reduced in the serum of these knockout mice. Further, DMBA treatment of these GABARAP knockout mice reduced the cellularity of the spleen and the growth of mammary glands through the induction of apoptosis. Gene expression profiling of mammary glands revealed significantly elevated levels of Xaf1, an apoptotic inducer and tumor-suppressor gene, in knockout mice. Furthermore, DMBA treatment triggered the upregulation of pro-apoptotic (Bid, Apaf1, Bax), cell death (Tnfrsf10b, Ripk1) and cell cycle inhibitor (Cdkn1a, Cdkn2c) genes in the mammary glands. Finally, tumor growth of B16 melanoma cells after subcutaneous inoculation was inhibited in GABARAP-deficient mice. Together, these data provide strong evidence for the involvement of GABARAP in tumorigenesis in vivo by delaying cell death and its associated immune-related response.

Asunto(s)

Apoptosis , Autofagia , Citocinas/metabolismo , Proteínas del Citoesqueleto/genética , Proteínas de la Membrana/genética , 9,10-Dimetil-1,2-benzantraceno/toxicidad , Proteínas Adaptadoras Transductoras de Señales , Animales , Apoptosis/efectos de los fármacos , Proteínas Reguladoras de la Apoptosis , Autofagia/efectos de los fármacos , Familia de las Proteínas 8 Relacionadas con la Autofagia/genética , Familia de las Proteínas 8 Relacionadas con la Autofagia/metabolismo , Carcinogénesis/efectos de los fármacos , Citocinas/genética , Proteínas del Citoesqueleto/deficiencia , Proteínas F-Box/genética , Proteínas F-Box/metabolismo , Femenino , Lipopolisacáridos/toxicidad , Linfocitos/citología , Linfocitos/inmunología , Linfocitos/metabolismo , Macrófagos/citología , Macrófagos/inmunología , Macrófagos/metabolismo , Glándulas Mamarias Animales/efectos de los fármacos , Glándulas Mamarias Animales/metabolismo , Glándulas Mamarias Animales/patología , Melanoma/metabolismo , Melanoma/patología , Proteínas de la Membrana/deficiencia , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas Asociadas a Microtúbulos/genética , Proteínas Asociadas a Microtúbulos/metabolismo , Transcriptoma/efectos de los fármacos , Factor de Crecimiento Transformador beta1/sangre