RESUMO
Recent studies have suggested that C-MYC may be an excellent therapeutic cancer target and a number of new agents targeting C-MYC are in preclinical development. Given most therapeutic regimes would combine C-MYC inhibition with genotoxic damage, it is important to assess the importance of C-MYC function for DNA damage signalling in vivo. In this study, we have conditionally deleted the c-Myc gene in the adult murine intestine and investigated the apoptotic response of intestinal enterocytes to DNA damage. Remarkably, c-Myc deletion completely abrogated the immediate wave of apoptosis following both ionizing irradiation and cisplatin treatment, recapitulating the phenotype of p53 deficiency in the intestine. Consistent with this, c-Myc-deficient intestinal enterocytes did not upregulate p53. Mechanistically, this was linked to an upregulation of the E3 Ubiquitin ligase Mdm2, which targets p53 for degradation in c-Myc-deficient intestinal enterocytes. Further, low level overexpression of c-Myc, which does not impact on basal levels of apoptosis, elicited sustained apoptosis in response to DNA damage, suggesting c-Myc activity acts as a crucial cell survival rheostat following DNA damage. We also identify the importance of MYC during DNA damage-induced apoptosis in several other tissues, including the thymus and spleen, using systemic deletion of c-Myc throughout the adult mouse. Together, we have elucidated for the first time in vivo an essential role for endogenous c-Myc in signalling DNA damage-induced apoptosis through the control of the p53 tumour suppressor protein.
Assuntos
Apoptose/genética , Enterócitos/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Animais , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Sobrevivência Celular/efeitos dos fármacos , Cisplatino/administração & dosagem , Dano ao DNA/efeitos dos fármacos , Dano ao DNA/efeitos da radiação , Enterócitos/efeitos dos fármacos , Enterócitos/efeitos da radiação , Humanos , Camundongos , Proteínas Proto-Oncogênicas c-myc/genética , Radiação IonizanteRESUMO
Lung cancer is the leading cause of cancer deaths worldwide with non small-cell lung cancer (NSCLC) accounting for 80% of all lung cancers. Although activating mutations in genes of the RAS-MAPK pathway occur in up to 30% of all NSCLC, the cooperating genetic lesions that are required for lung cancer initiation and progression remain poorly understood. Here we identify a role for the cell polarity regulator Scribble (Scrib) in NSCLC. A survey of genomic databases reveals deregulation of SCRIB in human lung cancer and we show that Scrib(+/-) mutant mice develop lung cancer by 540 days with a penetrance of 43%. To model NSCLC development in vivo, we used the extensively characterized LSL-KRas(G12D) murine model of NSCLC. We show that loss of Scrib and activated oncogenic KRas cooperate in vivo, resulting in more aggressive lung tumors, likely due to a synergistic elevation in RAS-MAPK signaling. Finally, we provide data consistent with immune infiltration having an important role in the acceleration of tumorigenesis in KRas(G12D) lung tumors following Scrib loss.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Transformação Celular Neoplásica/genética , Neoplasias Pulmonares/genética , Proteínas de Membrana/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Supressoras de Tumor/genética , Proteínas ras/genética , Animais , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Modelos Animais de Doenças , Progressão da Doença , Ativação Enzimática , Dosagem de Genes , Heterozigoto , Humanos , Immunoblotting , Imuno-Histoquímica , Peptídeos e Proteínas de Sinalização Intracelular/genética , Perda de Heterozigosidade , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Mutantes , Análise de Sequência com Séries de Oligonucleotídeos , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Proteínas ras/metabolismoRESUMO
The concept of a cancer stem cell is not a new one, being first suggested over 100 years ago. Over recent years the concept has enjoyed renewed enthusiasm, partly because of our growing understanding of the nature of somatic stem cells, but also because of a growing realisation that the development of strategies that target cancer stem cells may offer considerable advantages over conventional approaches. However, despite this renewed enthusiasm the existence of cancer stem cells remains controversial in many tumour types and any potential relationship to the normal stem cell pool remains poorly defined. This review summarises key elements of our understanding of the normal stem cell populations within animal models of the predominant cancer prone epithelial tissues, and further investigates the potential links between these populations and putative cancer stem cells.
