RESUMO
Background: The chromosome 1p32p31 deletion syndrome is a contiguous gene disorder with a variable phenotype characterized by brain malformations with or without urinary tract defects, besides neurodevelopmental delay and dysmorphisms. An expanded phenotype was proposed based on additional findings, including one previous report of a patient presenting with moyamoya disease. Case Presentation: The authors report a patient presenting with early neurodevelopmental delay, hydrocephalus, renal malformation, and dysmorphisms. After presenting with a sudden choreic movement disorder, the neuroimaging investigation revealed an ischemic stroke, moyamoya disease, and bilateral incomplete hippocampal inversion. Chromosomal microarray analysis revealed a deletion of 13.2 Mb at 1p31.3p32.2, compatible with the contiguous gene syndrome caused by microdeletions of this region. Discussion/Conclusion: This is the second report of a patient who developed Moyamoya disease and the first to describe bilateral incomplete hippocampal inversion in this microdeletion syndrome.
RESUMO
The protein p32 (C1QBP) is a multifunctional and multicompartmental homotrimer that is overexpressed in many cancer types, including colon cancer. High expression levels of C1QBP are negatively correlated with the survival of patients. Previously, we demonstrated that C1QBP is an essential promoter of migration, chemoresistance, clonogenic, and tumorigenic capacity in colon cancer cells. However, the mechanisms underlying these functions and the effects of specific C1QBP protein inhibitors remain unexplored. Here, we show that the specific pharmacological inhibition of C1QBP with the small molecule M36 significantly decreased the viability rate, clonogenic capacity, and proliferation rate of different colon cancer cell lines in a dose-dependent manner. The effects of the inhibitor of C1QBP were cytostatic and non-cytotoxic, inducing a decreased activation rate of critical pro-malignant and mitogenic cellular pathways such as Akt-mTOR and MAPK in RKO colon cancer cells. Additionally, treatment with M36 significantly affected the mitochondrial integrity and dynamics of malignant cells, indicating that p32/C1QBP plays an essential role in maintaining mitochondrial homeostasis. Altogether, our results reinforce that C1QBP is an important oncogene target and that M36 may be a promising therapeutic drug for the treatment of colon cancer.
Assuntos
Neoplasias do Colo , Citostáticos , Humanos , Citostáticos/farmacologia , Mitógenos/farmacologia , Transdução de Sinais , Proteínas Mitocondriais/metabolismo , Proliferação de Células , Proteínas de Transporte/metabolismoRESUMO
P32/gC1qR/HABP1 is a doughnut-shaped acidic protein, highly conserved in eukaryote evolution and ubiquitous in the organism. Although its canonical subcellular localization is the mitochondria, p32 can also be found in the cytosol, nucleus, cytoplasmic membrane, and it can be secreted. Therefore, it is considered a multicompartmental protein. P32 can interact with many physiologically divergent ligands in each subcellular location and modulate their functions. The main ligands are C1q, hyaluronic acid, calreticulin, CD44, integrins, PKC, splicing factor ASF/SF2, and several microbial proteins. Among the functions in which p32 participates are mitochondrial metabolism and dynamics, apoptosis, splicing, immune response, inflammation, and modulates several cell signaling pathways. Notably, p32 is overexpressed in a significant number of epithelial tumors, where its expression level negatively correlates with patient survival. Several studies of gain and/or loss of function in cancer cells have demonstrated that p32 is a promoter of malignant hallmarks such as proliferation, cell survival, chemoresistance, angiogenesis, immunoregulation, migration, invasion, and metastasis. All of this strongly suggests that p32 is a potential diagnostic molecule and therapeutic target in cancer. Indeed, preclinical advances have been made in developing therapeutic strategies using p32 as a target. They include tumor homing peptides, monoclonal antibodies, an intracellular inhibitor, a p32 peptide vaccine, and p32 CAR T cells. These advances are promising and will allow soon to include p32 as part of targeted cancer therapies.
Assuntos
Proteínas Mitocondriais , Neoplasias , Proteínas de Transporte , Humanos , Ligantes , Mitocôndrias/metabolismo , Proteínas Mitocondriais/metabolismo , Neoplasias/patologiaRESUMO
p32 is a multifunctional and multicompartmental protein that has been found upregulated in numerous adenocarcinomas, including colorectal malignancy. High levels of p32 expression have been correlated with poor prognosis in colorectal cancer. However, the functions performed by p32 in colorectal cancer have not been characterized. Here we show that p32 is overexpressed in colorectal cancer cell lines compared to non-malignant colon cells. Colon cancer cells also display higher nuclear levels of p32 than nuclear levels found in non-malignant cells. Moreover, we demonstrate that p32 regulates the expression levels of genes tightly related to malignant phenotypes such as HAS-2 and PDCD4. Remarkably, we demonstrate that knockdown of p32 negatively affects Akt/mTOR signaling activation, inhibits the migration ability of colon malignant cells, and sensitizes them to cell death induced by oxidative stress and chemotherapeutic agents, but not to cell death induced by nutritional stress. In addition, knockdown of p32 significantly decreased clonogenic capacity and in vivo tumorigenesis in a xenograft mice model. Altogether, our results demonstrate that p32 is an important promoter of malignant phenotype in colorectal cancer cells, suggesting that it could be used as a therapeutic target in colorectal cancer treatment.
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RNA-binding proteins (RBPs) are involved in many aspects of mRNA metabolism such as splicing, nuclear export, translation, silencing, and decay. To cope with these tasks, these proteins use specialized domains such as the RNA recognition motif (RRM), the most abundant and widely spread RNA-binding domain. Although this domain was first described as a dedicated RNA-binding moiety, current evidence indicates these motifs can also engage in direct protein-protein interactions. Here, we discuss recent evidence describing the interaction between the RRM of the trypanosomatid RBP UBP1 and P22, the homolog of the human multifunctional protein P32/C1QBP. Human P32 was also identified while performing a similar interaction screening using both RRMs of TDP-43, an RBP involved in splicing regulation and Amyotrophic Lateral Sclerosis. Furthermore, we show that this interaction is mediated by RRM1. The relevance of this interaction is discussed in the context of recent TDP-43 interactomic approaches that identified P32, and the numerous evidences supporting interactions between P32 and RBPs. Finally, we discuss the vast universe of interactions involving P32, supporting its role as a molecular chaperone regulating the function of its ligands.
Assuntos
Proteínas de Transporte/metabolismo , Proteínas Mitocondriais/metabolismo , Proteínas de Protozoários/metabolismo , Proteínas de Ligação a RNA/metabolismo , Trypanosoma/metabolismo , Sítios de Ligação , Linhagem Celular , Humanos , Motivos de Nucleotídeos , Ligação Proteica , Mapeamento de Interação de Proteínas , Transporte Proteico , RNA Mensageiro/química , RNA Mensageiro/genética , RNA Mensageiro/metabolismoRESUMO
Avian Infectious Laryngotracheitis, caused by Infectious Laryngotracheitis Virus (ILTV), has been reported for decades in Brazilian laying and broiler flocks. More recently, outbreaks have occurred in São Paulo State. This study reports the application of PCR and DNA sequencing targeted to the p32 gene of ILTV using laying chicken samples from Bastos, São Paulo, Brazil. Three out of four field samples were positive by PCR. DNA sequencing of two samples evidenced homology of the amplified fragments with the p32 gene of ILTV. The results definitely confirmed the presence of ILTV in the birds during the outbreak. Further studies are needed to establish the sources of infection and to determine whether the detected virus was originated from vaccine or field virus strains.
RESUMO
Avian Infectious Laryngotracheitis, caused by Infectious Laryngotracheitis Virus (ILTV), has been reported for decades in Brazilian laying and broiler flocks. More recently, outbreaks have occurred in São Paulo State. This study reports the application of PCR and DNA sequencing targeted to the p32 gene of ILTV using laying chicken samples from Bastos, São Paulo, Brazil. Three out of four field samples were positive by PCR. DNA sequencing of two samples evidenced homology of the amplified fragments with the p32 gene of ILTV. The results definitely confirmed the presence of ILTV in the birds during the outbreak. Further studies are needed to establish the sources of infection and to determine whether the detected virus was originated from vaccine or field virus strains.