RESUMO
Data emerged from the last 20 years of basic research on tumor antigens positioned the type I MAGE (Melanoma Antigen GEnes - I or MAGE-I) family as cancer driver factors. MAGE-I gene expression is mainly restricted to normal reproductive tissues. However, abnormal re-expression in cancer unbalances the cell status towards enhanced oncogenic activity or reduced tumor suppression. Anomalous MAGE-I gene re-expression in cancer is attributed to altered epigenetic-mediated chromatin silencing. Still, emerging data indicate that MAGE-I can be regulated at protein level. Results from different laboratories suggest that after its anomalous re-expression, specific MAGE-I proteins can be regulated by well-known signaling pathways or key cellular processes that finally potentiate the cancer cell phenotype. Thus, MAGE-I proteins both regulate and are regulated by cancer-related pathways. Here, we present an updated review highlighting the recent findings on the regulation of MAGE-I by oncogenic pathways and the potential consequences in the tumor cell behavior.
Assuntos
Melanoma , Proteínas de Neoplasias , Humanos , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Antígenos de Neoplasias/genéticaRESUMO
An essential requirement for cells to sustain a high proliferating rate is to be paired with enhanced protein synthesis through the production of ribosomes. For this reason, part of the growth-factor signaling pathways, are devoted to activate ribosome biogenesis. Enhanced production of ribosomes is a hallmark in cancer cells, which is boosted by different mechanisms. Here we report that the nucleolar tumor-protein MageB2, whose expression is associated with cell proliferation, also participates in ribosome biogenesis. Studies carried out in both siRNA-mediated MageB2 silenced cells and CRISPR/CAS9-mediated MageB2 knockout (KO) cells showed that its expression is linked to rRNA transcription increase independently of the cell proliferation status. Mechanistically, MageB2 interacts with phospho-UBF, a protein which causes the recruitment of RNA Pol I pre-initiation complex required for rRNA transcription. In addition, cells expressing MageB2 displays enhanced phospho-UBF occupancy at the rDNA gene promoter. Proteomic studies performed in MageB2 KO cells revealed impairment in ribosomal protein (RPs) content. Functionally, enhancement in rRNA production in MageB2 expressing cells, was directly associated with an increased dynamic in protein synthesis. Altogether our results unveil a novel function for a tumor-expressed protein from the MAGE-I family. Findings reported here suggest that nucleolar MageB2 might play a role in enhancing ribosome biogenesis as part of its repertoire to support cancer cell proliferation.
Assuntos
Antígenos de Neoplasias/metabolismo , Proteínas de Neoplasias/metabolismo , Ribossomos/metabolismo , Antígenos de Neoplasias/fisiologia , Linhagem Celular Tumoral , Nucléolo Celular/metabolismo , Proliferação de Células/genética , DNA Ribossômico/genética , DNA Ribossômico/metabolismo , Células HCT116 , Células HEK293 , Humanos , Proteínas de Neoplasias/fisiologia , Neoplasias/genética , Neoplasias/metabolismo , Proteínas Nucleares/metabolismo , Proteínas Pol1 do Complexo de Iniciação de Transcrição/metabolismo , Regiões Promotoras Genéticas/genética , Biossíntese de Proteínas , Processamento de Proteína Pós-Traducional , Proteômica , RNA Polimerase I/metabolismo , RNA Ribossômico/biossíntese , Ribossomos/genética , Transcrição Gênica/genéticaRESUMO
A dimer of the heat-shock protein of 90-kDa (Hsp90) represents the critical core of the chaperone complex associated to the glucocorticoid receptor (GR) oligomer. The C-terminal end of the Hsp90 dimer shapes a functional acceptor site for co-chaperones carrying tetratricopeptide repeat (TPR) domains, where they bind in a mutually exclusive and competitive manner. They impact on the biological properties of the GRâ¢Hsp90 complex and are major players of the GR transport machinery. Recently, we showed that the overexpression of a chimeric TPR peptide influences the subcellular distribution of GR. In this study, the functional role of endogenous proteins carrying TPR or TPR-like sequences on GR subcellular distribution was characterized. It is demonstrated that, contrarily to the positive influence of FKBP52 on GR nuclear accumulation, FKBP51 and 14-3-3 impaired this property. While SGT1α showed no significant effect, the overexpression of the Ser/Thr phosphatase PP5 resulted in a nearly equal nuclear-cytoplasmic redistribution of GR rather than its typical cytoplasmic localization in the absence of steroid. This observation led to analyse the influence of the phosphorylation status of GR, which resulted not linked to its nucleo-cytoplasmic shuttling mechanism. Nonetheless, it was evidenced that both PP5 and FKBP52 are related to the anchorage of the GR to nucleoskeleton structures. The influence of these TPR domain proteins on the steroid-dependent transcriptional activity of GR was also characterized. It is postulated that the pleiotropic actions of the GR in different cell types may be the consequence of the relative abundance of different TPR-domain interacting co-chaperones.
Assuntos
Núcleo Celular/metabolismo , Citoplasma/metabolismo , Chaperonas Moleculares/química , Chaperonas Moleculares/metabolismo , Receptores de Glucocorticoides/metabolismo , Regulação da Expressão Gênica , Células HEK293 , Humanos , Ligação Proteica , Domínios Proteicos , Transporte Proteico , Receptores de Glucocorticoides/genética , Repetições de TetratricopeptídeosRESUMO
Normal-to-tumor cell transition is accompanied by changes in gene expression and signal transduction that turns the balance toward cancer-cell phenotype, eluding by different mechanisms, the response of tumor-suppressor genes. Here, we observed that MageC2, a MAGE-I protein able to regulate the p53 tumor-suppressor, is accumulated upon MEK/ERK MAPK activation. Overexpression of H-RasV12 oncogene causes an increase in MageC2 protein that is prevented by pharmacologic inhibition of MEK. Similarly, decrease in MageC2 protein levels is shown in A375 melanoma cells (which harbor B-RafV600E oncogenic mutation) treated with MEK inhibitors. MageC2 protein levels decrease when p14ARF is expressed, causing an Mdm2-independent upregulation of p53 transactivation. However, MageC2 is refractory to p14ARF-driven downregulation when H-RasV12 is co-expressed. Using MageC2 knockout A375 cells generated by CRISPR/CAS9 technology, we demonstrated the relevance of MageC2 protein in reducing p53 transcriptional activity in cells containing hyperactive MEK/ERK signaling. Furthermore, gene expression analysis performed in cancer-genomic databases, supports the correlation of reduced p53 transcriptional activity and high MageC2 expression, in melanoma cells containing Ras or B-Raf driver mutations. Data presented here suggest that MageC2 can be a functional target of the oncogenic MEK/ERK pathway to regulate p53.
Assuntos
Antígenos de Neoplasias/genética , Antígenos de Neoplasias/metabolismo , Melanoma/metabolismo , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Animais , Antígenos de Neoplasias/química , Linhagem Celular Tumoral , Inibidor p16 de Quinase Dependente de Ciclina/genética , Fibroblastos/citologia , Fibroblastos/metabolismo , Regulação Neoplásica da Expressão Gênica , Técnicas de Inativação de Genes , Células HEK293 , Humanos , Sistema de Sinalização das MAP Quinases , Melanoma/genética , Camundongos , Proteínas de Neoplasias/química , Estabilidade Proteica , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Ativação TranscricionalRESUMO
Dengue virus (DENV) threatens almost 70% of the world's population, with no therapeutic currently available. The severe, potentially lethal forms of DENV disease (dengue hemorrhagic fever/dengue shock syndrome) are associated with the production of high level of cytokines, elicited as part of the host antiviral response, although the molecular mechanisms have not been fully elucidated. We previously showed that infection by DENV serotype 2 (DENV2) disrupts promyelocytic leukemia (PML) gene product nuclear bodies (PML-NBs) after viral protein translation in infected cells. Apart from playing a key role as the nucleating agent in forming PML-NBs, PML has antiviral activity against various viruses, including DENV. The present study builds on this work, showing for the first time that all four DENV serotypes elicit PML-NB breakdown. Importantly, we show for the first time that of the nuclear localizing proteins of DENV, DENV non-structural protein (NS) 5 polymerase alone is sufficient to elicit PML-NB disassembly, in part through complexing with PML isoforms III and IV, but not other PML isoforms or other PML-NB components. The results raise the possibility that PML-NB disruption by nuclear localized NS5 contributes to DENV's suppression of the host antiviral response.
Assuntos
Núcleo Celular/metabolismo , Vírus da Dengue/fisiologia , Dengue/metabolismo , Dengue/virologia , Interações Hospedeiro-Patógeno , Proteína da Leucemia Promielocítica/metabolismo , Proteínas não Estruturais Virais/metabolismo , Linhagem Celular , Vírus da Dengue/classificação , Expressão Gênica , Humanos , Ligação Proteica , Isoformas de Proteínas , Transporte Proteico , Sorogrupo , Proteínas não Estruturais Virais/genética , Replicação ViralRESUMO
MAGE-A (Melanoma Antigen Genes-A) are tumor-associated proteins with expression in a broad spectrum of human tumors and normal germ cells. MAGE-A gene expression and function are being increasingly investigated to better understand the mechanisms by which MAGE proteins collaborate in tumorigenesis and whether their detection could be useful for disease prognosis purposes. Alterations in epigenetic mechanisms involved in MAGE gene silencing cause their frequent co-expression in tumor cells. Here, we have analyzed the effect of MAGE-A gene co-expression and our results suggest that MageA6 can potentiate the androgen receptor (AR) co-activation function of MageA11. Database search confirmed that MageA11 and MageA6 are co-expressed in human prostate cancer samples. We demonstrate that MageA6 and MageA11 form a protein complex resulting in the stabilization of MageA11 and consequently the enhancement of AR activity. The mechanism involves association of the Mage A6-MHD domain to MageA11, prevention of MageA11 ubiquitinylation on lysines 240 and 245 and decreased proteasome-dependent degradation. We experimentally demonstrate here for the first time that two MAGE-A proteins can act together in a non-redundant way to potentiate a specific oncogenic function. Overall, our results highlight the complexity of the MAGE gene networking in regulating cancer cell behavior.
Assuntos
Antígenos de Neoplasias/genética , Antígenos de Neoplasias/metabolismo , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Antígenos de Neoplasias/química , Linhagem Celular Tumoral , Expressão Gênica , Humanos , Masculino , Complexos Multiproteicos/química , Complexos Multiproteicos/genética , Complexos Multiproteicos/metabolismo , Proteínas de Neoplasias/química , Neoplasias Embrionárias de Células Germinativas/genética , Neoplasias Embrionárias de Células Germinativas/metabolismo , Domínios e Motivos de Interação entre Proteínas , Estabilidade Proteica , Receptores Androgênicos/metabolismo , Neoplasias Testiculares/genética , Neoplasias Testiculares/metabolismo , UbiquitinaçãoRESUMO
Since its discovery in 1991, the knowledge about the tumor specific melanoma antigen gene (MAGE-I) family has been continuously increasing. Initially, MAGE-I proteins were considered as selective targets for immunotherapy. More recently, emerging data obtained from different cellular mechanisms controlled by MAGE-I proteins suggest a key role in the regulation of important pathways linked to cell proliferation. This is in part due to the ability of some MAGE-I proteins to control the p53 tumor suppressor. In this review, we focus on the mechanisms proposed to explain how MAGE-I proteins affect p53 functions.