RESUMO
The melanoma antigen (MAGE) family consists of more than 60 genes, many of which are cancer-testis antigens that are highly expressed in cancer and play a critical role in tumorigenesis. However, the biochemical and cellular functions of this enigmatic family of proteins have remained elusive. Here, we identify really interesting new gene (RING) domain proteins as binding partners for MAGE family proteins. Multiple MAGE family proteins bind E3 RING ubiquitin ligases with specificity. The crystal structure of one of these MAGE-RING complexes, MAGE-G1-NSE1, reveals structural insights into MAGE family proteins and their interaction with E3 RING ubiquitin ligases. Biochemical and cellular assays demonstrate that MAGE proteins enhance the ubiquitin ligase activity of RING domain proteins. For example, MAGE-C2-TRIM28 is shown to target p53 for degradation in a proteasome-dependent manner, consistent with its tumorigenic functions. These findings define a biochemical and cellular function for the MAGE protein family.
Assuntos
Antígenos Específicos de Melanoma/metabolismo , Domínios RING Finger , Ubiquitina-Proteína Ligases/metabolismo , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/metabolismo , Biocatálise , Proteínas de Transporte/química , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Linhagem Celular , Linhagem Celular Tumoral , Núcleo Celular/metabolismo , Cristalografia por Raios X , Citoplasma/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/química , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Antígenos Específicos de Melanoma/química , Antígenos Específicos de Melanoma/genética , Modelos Moleculares , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Ligação Proteica/fisiologia , Domínios e Motivos de Interação entre Proteínas/fisiologia , Estrutura Quaternária de Proteína , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Transfecção , Proteína 28 com Motivo Tripartido , Proteína Supressora de Tumor p53/metabolismo , Ubiquitina-Proteína Ligases/química , Ubiquitina-Proteína Ligases/genética , UbiquitinaçãoRESUMO
OBJECTIVE: To examine physician communication associated with prognosis discussion with cancer patients. METHODS: We conducted a study of physician-patient communication using trained actors. Thirty-nine physicians, including 19 oncologists and 20 family physicians participated in the study. Actors carried two hidden digital recorders to unannounced visits. We coded recordings for eliciting and validating patient concerns, attentive voice tone, and prognosis talk. RESULTS: Actor adherence to role averaged 92% and the suspected detection rate was 14%. In a multiple regression, eliciting and validating patient concerns (beta=.40, C.I.=0.11-0.68) attentiveness (beta=.32, C.I.=0.06-0.58) and being an oncologist vs. a family physician (beta=.33, C.I.=0.33-1.36) accounted for 46% of the variance in prognosis communication. CONCLUSION: Eliciting and validating patient concerns and attentiveness voice tone is associated with increased discussion of cancer patient prognosis as is physician specialty. PRACTICE IMPLICATIONS: Eliciting and validating patient concerns and attentive voice tone may be markers of physician willingness to discuss emotionally difficult topics. Educating physicians about mindful practice may increase their ability to collect important information and to attend to patient concerns.