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Glioblastomas are the most common brain malignancy occurring in adults with the worst prognosis. Several obstacles have prevented the development of efficacious treatment strategies. Due to the insidious nature of these malignancies, tumors are not typically detected until late in the disease. Further, the delicate nature of surrounding normal brain tissue makes surgery and treatment with cytotoxic chemotherapeutics detrimental to the patient's quality of life. Despite decades of research and aggressive therapeutic strategies, most patients will develop recurrent tumors and succumb to the disease within 1 year of diagnosis. An enhanced understanding of the molecular interplay among tumor suppressors and oncoproteins can greatly contribute to the development of novel therapeutics that will extend life expectancies. The most common abnormality in these tumors is mutation of the p53 gene (TP53). Due to the expansive network of p53-responsive genes, loss of functional p53 prohibits the cell to the ability to regain control of aberrant proliferation in response to oncogenic stresses. Accordingly, glioblastomas have developed several mechanisms to inactivate this potent tumor suppressor. Similar to oncoproteins, viral regulatory proteins utilize p53 to prevent cell cycle arrest. One such example is the protein associated with the human polyoma virus, JC Virus (JCV). JCV is the etiologic agent of the fatal demyelinating disorder, Progressive Multifocal Leukoencephalopathy (PML), seen in severely immunocompromised patients. Infection of oligodendrocytes with JCV leads to their lytic destruction and the development of white matter lesions in PML patients. Its main regulatory protein, large tumor antigen (T-antigen), targets p53 to retain cells in a virus-producing state, thereby conveying an accidental oncogenicity. JCV T-antigen transgenic mice develop a multitude of CNS tumors, including malignant peripheral nerve sheath tumors similar to patients with a form of Neurofibromatosis. Neurofibromatosis types 1 and 2 are inherited cancer disorders resulting from the inactivation of their specific tumor suppressor genes, NF1 and NF2, respectively. Inactivation of the NF2 gene, results in the development of several multiple benign nervous system tumors. Traditionally, NF2 is viewed as a scaffolding protein primarily located at the plasma membrane, where it prevents excessive signaling via several cell surface receptors and their cytoplasmic kinases. NF2 links receptors at the plasma membrane to their cytoplasmic kinases to facilitate contact inhibition. However, NF2 can also interact with an array of cytoplasmic and a few nuclear proteins. To date, little is known about the function of NF2 in tumors not associated with NF2 syndrome. Loss of functional NF2 protein has become a staple of several sporadic cancers including mesotheliomas, and meningiomas. In glial cells, NF2 depletion results in hyperproliferation and development of oncogenic features. In the only prior report addressing the role of NF2 inactivation in glioblastoma, another group demonstrated that NF2 is a potent inhibitor of glioblastoma growth. Previously, our group has identified JCV T-antigen as a nuclear binding partner for NF2 in tumors derived from JCV T-antigen transgenic mice. The association of NF2 with T-antigen in neuronal origin tumors led us to hypothesize that NF2 could regulate the expression of the JCV T-antigen. Here, we report that NF2 suppresses T-antigen protein expression in U-87 MG human glioblastoma cells, which subsequently reduces T-antigen-mediated regulation of the JCV promoter. When T-antigen mRNA was quantified, it was determined that increasing expression of NF2 correlated with an accumulation of T-antigen mRNA; however, a decrease in T-antigen at the protein level was observed. NF2 was found to promote degradation of ubiquitin-bound T-antigen protein via a proteasome dependent pathway concomitant with the accumulation of the JCV early mRNA encoding T-antigen. The interaction between T-antigen and NF2 maps to the FERM domain of NF2 domain of NF2, which has been shown previously to be responsible for its tumor suppressor activity. Co-immunoprecipitation assays performed on a glioblastoma cell line revealed a ternary complex consisting of NF2, T-antigen, and the tumor suppressor protein, p53. Furthermore, these proteins were detected in various degrees in tumor specimens from patients, suggesting that these associations may occur in vivo. Collectively, these results demonstrate that NF2 negatively regulates JCV T-antigen expression by proteasome-mediated degradation, and suggest a novel role for NF2 as a suppressor of JCV T-antigen-induced oncogenesis. Studies in mouse and human tumors have inferred a relationship between NF2 and the primary target for JCV T-antigen, p53. In mouse models of cancer, concurrent loss of NF2 and p53 genes generates a highly malignant phenotype. Other groups reported that loss of NF2 and p53 in human tumors correlated with enhanced tumor grade. In transformed fibroblasts, NF2 can enhance the expression of p53 and promote p53-mediated apoptosis. However, the molecular details of the NF2 and p53 relationship have not yet been elucidated. Based on our data and previous literature, we believed that there is a tumor suppressive synergy that exists between NF2 and p53. Contrary to our expectations, we discovered that NF2 overexpression in U-87 MG cells results in the decline in p53 expression. We observed this effect in the p53-null cell line, Saos2, and in the presence of proteasome inhibitors. Further, we determined that NF2 utilizes cysteine proteases as part of a post translational mechanism to suppress p53 expression. Mutant p53, present in many glioblastomas, was resistant to NF2-mediated degradation. Additionally, we determined that p53 can reciprocally repress NF2 expression, by a post translational mechanism, independent of the proteasome, lysosome, or cysteine proteases. NF2 conformation mutants, S518A and S518D, can both degrade p53 and localize to the cytoplasm. However, the constitutively inactive, open form of NF2, S518D is resistant to p53-mediated degradation. NF2 and p53 do not directly interact, yet we were able to detect these proteins in the same patient glioblastoma samples. Using a conformation-specific antibody, we speculate that the majority of our glioblastoma samples may contain mutated p53. This novel relationship between NF2 and p53 we believe will have strong implications for chemotherapeutic sensitization of these typically resistant tumors. Cumulatively, these studies will provide evidence for novel tumor suppressive roles for NF2 and a greater understanding of the molecular events that shape glioblastoma progression. / Biomedical Neuroscience

Base teórica: A qualidade de vida é uma variável amplamente estudada nas ciências da saúde e tem se tornado, cada vez mais, um indicativo importante na avaliação dos estados e desfechos de saúde. As doenças crônicas se caracterizam por curso prolongado, por vezes acompanhando o portador por toda sua vida, o que pode influenciar a percepção que o indivíduo tem de si mesmo e de sua vida. A Neurofibromatose tipo 1 (NF1) é uma doença crônica, genética, que atinge cerca de 1:3500 nascimentos. Além de ser uma doença que acarreta uma maior predisposição ao desenvolvimento de tumores, a NF1 possui sintomas físicos de fácil identificação. Objetivo: O presente estudo visa estudar a qualidade de vida e algumas variáveis emocionais de pessoas com neurofibromatose tipo 1. Método: Trata-se de um estudo transversal. Foram avaliadas as variáveis de qualidade de vida genérica (WHOQOL-bref e SF-36), qualidade de vida específica para pessoas com problemas de pele (DLQI-bra), sintomas depressivos (BDI), sintomas de ansiedade(BAI), percepção de suporte familiar (IPSF) e estratégias de enfrentamento (Inventário de Estratégias de Coping de Folkman e Lazarus). Os participantes deste estudo também foram avaliados quanto à gravidade (Escala de Riccardi) e visibilidade dos sintomas da doença (Ablon). Resultados: Foram coletados dados de 71 pacientes adultos com NF1. Do total 60,0% da amostra foram pessoas do sexo feminino, a média de idade foi de ± 40,36 anos. Dos 52 pacientes avaliados pela escala de Riccardi, 11,3% apresentou gravidade leve, 40,4% gravidade moderada, 42% sintomas graves de gravidade e 6,5% sintomas muito graves da doença. Com relação a visibilidade dos sintomas medidos pela escala de Ablon, 36,5% apresentam visibilidade leve de sintomas, 30,8% visibilidade moderada e 32.7% visibilidade severa dos sintomas. Conclusão: Os resultados da avaliação de qualidade de vida de pessoas com NF1, ao serem comparados com os dados normativos para amostra, não apresentou diferença estatisticamente significativa. A análise dos sintomas depressivos indicou que grande parte dos entrevistados apresentam sintomas leves de depressão e os dados da escala BAI referente aos sintomas de ansiedade constatou que a média dos entrevistados apresentam sintomas graves de ansiedade, podendo sugerir que a ansiedade seja uma característica importante dessa população. As estratégias de enfrentamento mais utilizadas por esta população foram a reavaliação e o suporte social. Com relação aos resultados da percepção de suporte familiar, podemos perceber que os dados da amostra não apresentaram diferença significativa ao serem comparados com os dados normativos da escala. / Theoretical basis: Quality of life is an important studied variable in health sciences and has become an important indicator in assessing states and health outcome. Chronic diseases are characterized by a prolonged course, sometimes accompanying the carrier all his life, which can influence the perception that the individual has of himself and of his life. The neurofibromatosis type 1 (NF1) is a chronic and genetics condition that affects about 1: 3500 births. Besides being a disease that leads to a greater predisposition to develop tumors, NF1 has physical symptoms of easy identification. Objective: This project aims to study the quality of life and emotional variables of people with neurofibromatosis type 1. Method: This is an observational study. The overall quality of life variables were evaluated (WHOQOL-bref and SF-36), specific quality of life for people with skin problems (DLQI-bra), depressive symptoms (BDI), anxiety symptoms (BAI), perception of family supports (IPSF) and coping strategies (coping strategies Inventory of Folkman and Lazarus). The participants were also evaluated for the severity (Riccardi Scale) and visibility of disease symptoms (Ablon). Results: Were collected data from 71 adults patients with NF1. From all sample 60% were female. The mean age was ± 40.36 years . Of the 52 patients evaluated for Riccardi scale , 11.3 % had mild severity , 40.4 % moderate severity , 42% Severity of symptoms and 6.5 % symptoms very severe. The data of the visibility of the symptoms were measure by Ablon scale , 36.5 % have mild symptoms visibility , 30.8 % moderate and 32.7 % severe visibility of symptoms. Conclusion: The results of the quality of life of people with NF1, when compared with the normative data for sample, indicate no statistically significant difference. The analysis of depressive symptoms indicated that the majority of respondents have mild symptoms of depression and the BAI scale data related to symptoms of anxiety found that the average of respondents have severe anxiety symptoms and may suggest that anxiety can be an important feature of this population. Coping strategies most used by this population were the re-evaluation and social support. Regarding the results of the perception of family support, we can see that the sample data showed no significant difference when compared with the normative data range.

Neurofibromin (NF1) is a 2,818aa protein encoded by the very large NF1 tumour suppressor gene located on chromosome 17q11.2. Loss of function mutations and deletions in NF1 underlie Neurofibromatosis type-1 (NF-1) - the most common inherited syndrome of the nervous system in humans with a birth incidence of 1:3,000. The most visible feature of NF-1 is the neoplastic manifestations known as neurofibromas, however, the syndrome is also characterized by pigmentary defects, peripheral motor dysfunction, learning disabilities and several developmental abnormalities. The molecular etiology of many of these non-neoplastic phenotypes remains unknown. Here we demonstrate that the Tubulin Binding Domain (TBD) of NF1 is a binding partner of the Leucine Rich Pentatrico Peptide Repeat motif-Containing protein (LRPPRC) and cytoplasmic Dynein Heavy Chain (DHC). The NF1-LRPPRC interaction is of high significance as it links NF-1 with Leigh’s Syndrome, French Canadian variant (LSFC) – an autosomal recessive neurodegenerative disorder that arises due to mutations in the LRPPRC gene. This interaction occurs as part of an RNA granule complex, and use of transgenic mouse models establishes an important role of NF1 and LRPPRC in peripheral nerve development. The NF1-DHC interaction is of importance in melanocytes where our studies suggest a possible role in melanosome localization, disruptions in which may underlie the abnormal pigmentary features known as café-au-lait macules that are commonly associated with NF-1. The validation of LRPPRC and DHC as novel NF1 interactors reveal new roles of NF1, which open the door to better understanding the molecular mechanisms that underlie the myriad of NF-1 manifestations.