RESUMO
Histone H2B monoubiquitination (H2Bub1) is centrally involved in gene regulation. The deubiquitination module (DUBm) of the SAGA complex is a major regulator of global H2Bub1 levels, and components of this DUBm are linked to both neurodegenerative diseases and cancer. Unexpectedly, we find that ablation of USP22, the enzymatic center of the DUBm, leads to a reduction, rather than an increase, in global H2bub1 levels. In contrast, depletion of non-enzymatic components, ATXN7L3 or ENY2, results in increased H2Bub1. These observations led us to discover two H2Bub1 DUBs, USP27X and USP51, which function independently of SAGA and compete with USP22 for ATXN7L3 and ENY2 for activity. Like USP22, USP51 and USP27X are required for normal cell proliferation, and their depletion suppresses tumor growth. Our results reveal that ATXN7L3 and ENY2 orchestrate activities of multiple deubiquitinating enzymes and that imbalances in these activities likely potentiate human diseases including cancer.
Assuntos
Neoplasias da Mama/enzimologia , Proliferação de Células , Enzimas Desubiquitinantes/metabolismo , Histonas/metabolismo , Fatores de Transcrição/metabolismo , Carga Tumoral , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Enzimas Desubiquitinantes/genética , Endopeptidases/genética , Endopeptidases/metabolismo , Feminino , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Genótipo , Células HEK293 , Humanos , Células MCF-7 , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Fenótipo , Interferência de RNA , Transdução de Sinais , Tioléster Hidrolases/genética , Tioléster Hidrolases/metabolismo , Fatores de Tempo , Fatores de Transcrição/genética , Transfecção , Ubiquitina Tiolesterase , Proteases Específicas de Ubiquitina/genética , Proteases Específicas de Ubiquitina/metabolismo , UbiquitinaçãoRESUMO
The Spt-Ada-Gcn5-acetyltransferase (SAGA) chromatin-modifying complex possesses acetyltransferase and deubiquitinase activities. Within this modular complex, Ataxin-7 anchors the deubiquitinase activity to the larger complex. Here we identified and characterized Drosophila Ataxin-7 and found that reduction of Ataxin-7 protein results in loss of components from the SAGA complex. In contrast to yeast, where loss of Ataxin-7 inactivates the deubiquitinase and results in increased H2B ubiquitination, loss of Ataxin-7 results in decreased H2B ubiquitination and H3K9 acetylation without affecting other histone marks. Interestingly, the effect on ubiquitination was conserved in human cells, suggesting a novel mechanism regulating histone deubiquitination in higher organisms. Consistent with this mechanism in vivo, we found that a recombinant deubiquitinase module is active in the absence of Ataxin-7 in vitro. When we examined the consequences of reduced Ataxin-7 in vivo, we found that flies exhibited pronounced neural and retinal degeneration, impaired movement, and early lethality.
Assuntos
Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Neurônios/patologia , Retina/patologia , Sequência de Aminoácidos , Animais , Ataxina-7 , Drosophila melanogaster/enzimologia , Células HeLa , Histonas/metabolismo , Humanos , Longevidade/genética , Modelos Moleculares , Dados de Sequência Molecular , Complexos Multiproteicos/genética , Proteínas do Tecido Nervoso/química , Proteínas do Tecido Nervoso/deficiência , Regiões Promotoras Genéticas/genética , Estrutura Quaternária de Proteína , Alinhamento de Sequência , Proteases Específicas de Ubiquitina/genética , Proteases Específicas de Ubiquitina/metabolismo , UbiquitinaçãoRESUMO
CpG dinucleotides are mutational hotspots associated with cancer and genetic diseases. Thymine DNA glycosylase (TDG) plays an integral role in CpG maintenance by excising mispaired thymine and uracil in a CpG context and also participates in transcriptional regulation via gene-specific CpG demethylation and functional interactions with the transcription machinery. Here, we report that protein kinase C alpha (PKCalpha) interacts with TDG and phosphorylates amino-terminal serine residues adjacent to lysines acetylated by CREB-binding protein (CBP) and p300 (CBP/p300). We establish that acetylation and phosphorylation are mutually exclusive, and their interplay dramatically alters the DNA mispair-processing functions of TDG. Remarkably, acetylation of the amino-terminal region abrogates high-affinity DNA binding and selectively prevents processing of G:T mispairs. In contrast, phosphorylation does not markedly alter DNA interactions, but may preserve G:T processing in vivo by preventing CBP-mediated acetylation. Mutational analysis suggests that the acetyl-acceptor lysines are not directly involved in contacting DNA, but may constitute a conformationally sensitive interface that modulates DNA interactions. These findings reveal opposing roles of CBP/p300 and PKCalpha in regulating the DNA repair functions of TDG and suggest that the interplay of these modifications in vivo may be critically important in the maintenance of CpG dinucleotides and epigenetic regulation.
Assuntos
Reparo do DNA , Timina DNA Glicosilase/metabolismo , Acetilação , Animais , Linhagem Celular , Humanos , Camundongos , Células NIH 3T3 , Fosforilação , Proteína Quinase C-alfa/metabolismo , Acetato de Tetradecanoilforbol/farmacologia , Timina DNA Glicosilase/químicaRESUMO
Ubiquitination refers to the conjugation of the ubiquitin protein (a small protein highly conserved among eukaryotes) to itself or to other proteins through differential use of ubiquitin's seven internal linkage sites or the amino-terminal amino group. By creating different chain lengths, an enormous proteomic diversity may be formed. This creates a signaling system that is central to controlling almost every conceivable protein function, from proteostasis to regulating enzyme function and everything in between. Protein ubiquitination is reversed through the activity of deubiquitinases (DUBs), enzymes that function to deconjugate ubiquitin from itself and protein substrates. DUBs are regulated through several mechanisms, from controlled subcellular localization within cells to developmental and tissue specific expression. Misregulation of DUBs has been implicated in several diseases including cancer and neurodegeneration. Here we present a brief overview of the role of DUBs in neurodegeneration, and as potential therapeutic targets.
Assuntos
Enzimas Desubiquitinantes/metabolismo , Doenças Neurodegenerativas/genética , Humanos , Doenças Neurodegenerativas/patologiaRESUMO
Spinocerebellar ataxia (SCA) type 7 (SCA7) is caused by a CAG trinucleotide repeat expansion in the ataxin 7 (ATXN7) gene, which results in polyglutamine expansion at the amino terminus of the ATXN7 protein. Although ATXN7 is expressed widely, the best characterized symptoms of SCA7 are remarkably tissue specific, including blindness and degeneration of the brain and spinal cord. While it is well established that ATXN7 functions as a subunit of the Spt Ada Gcn5 acetyltransferase (SAGA) chromatin modifying complex, the mechanisms underlying SCA7 remain elusive. Here, we review the symptoms of SCA7 and examine functions of ATXN7 that may provide further insights into its pathogenesis. We also examine phenotypes associated with polyglutamine expanded ATXN7 that are not considered symptoms of SCA7.
RESUMO
BACKGROUND: Steroid Receptor coactivator 3(SRC3) is an oncogene and a member of the SRC family of nuclear receptor coactivator proteins that mediate the transcriptional effects of nuclear hormone receptors as well as other transcription factors. RESULTS: We have used protein purification and mass spectrometry to identify the 53BP1 tumour suppressor as a novel SRC3-associated protein. Copurification was demonstrated using multiple antibodies, and was not dependent on DNA damage suggesting that SRC3 is not directly involved in the DNA damage response. However using chromatin immunoprecipitation(ChIP) and siRNA knockdown, we have demonstrated that both SRC3 and 53BP1 co-occupy the same region of the BRCA1 promoter and both are required for BRCA1 expression in HeLa cells. CONCLUSIONS: Our results suggest that both 53BP1 and SRC3 have a common function that converge at the BRCA1 promoter and possibly other genes important for DNA repair and genomic stability.
Assuntos
Genes BRCA1 , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Coativador 3 de Receptor Nuclear/metabolismo , Proteína de Ligação a CREB/metabolismo , Imunoprecipitação da Cromatina , Dano ao DNA , Técnicas de Silenciamento de Genes , Células HeLa , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/deficiência , Peptídeos e Proteínas de Sinalização Intracelular/genética , Espectrometria de Massas , Coativador 3 de Receptor Nuclear/deficiência , Coativador 3 de Receptor Nuclear/genética , Transporte Proteico , RNA Interferente Pequeno/genética , Proteína 1 de Ligação à Proteína Supressora de Tumor p53RESUMO
The Spt-Ada-Gcn5 Acetyltransferase (SAGA) chromatin modifying complex is a critical regulator of gene expression and is highly conserved across species. Subunits of SAGA arrange into discrete modules with lysine aceyltransferase and deubiquitinase activities housed separately. Mutation of the SAGA deubiquitinase module can lead to substantial biological misfunction and diseases such as cancer, neurodegeneration, and blindness. Here, we review the structure and functions of the SAGA deubiquitinase module and regulatory mechanisms acting to control these.
Assuntos
Enzimas Desubiquitinantes/metabolismo , Complexos Multienzimáticos/metabolismo , Transativadores/metabolismo , Ativação Transcricional , Fatores de Transcrição de p300-CBP/metabolismo , Animais , Arabidopsis/enzimologia , Aspergillus nidulans/enzimologia , Ataxina-7/genética , Cegueira/genética , Enzimas Desubiquitinantes/genética , Drosophila/enzimologia , Histonas/metabolismo , Humanos , Camundongos , Complexos Multienzimáticos/genética , Mutação , Neoplasias/genética , Doenças Neurodegenerativas/genética , Peptídeos/genética , Processamento de Proteína Pós-Traducional , RNA Polimerase II/metabolismo , Saccharomyces cerevisiae/enzimologia , Transativadores/genética , Fatores de Transcrição de p300-CBP/genéticaRESUMO
A hallmark of aging is loss of differentiated cell identity. Aged Drosophila midgut differentiated enterocytes (ECs) lose their identity, impairing tissue homeostasis. To discover identity regulators, we performed an RNAi screen targeting ubiquitin-related genes in ECs. Seventeen genes were identified, including the deubiquitinase Non-stop (CG4166). Lineage tracing established that acute loss of Non-stop in young ECs phenocopies aged ECs at cellular and tissue levels. Proteomic analysis unveiled that Non-stop maintains identity as part of a Non-stop identity complex (NIC) containing E(y)2, Sgf11, Cp190, (Mod) mdg4, and Nup98. Non-stop ensured chromatin accessibility, maintaining the EC-gene signature, and protected NIC subunit stability. Upon aging, the levels of Non-stop and NIC subunits declined, distorting the unique organization of the EC nucleus. Maintaining youthful levels of Non-stop in wildtype aged ECs safeguards NIC subunits, nuclear organization, and suppressed aging phenotypes. Thus, Non-stop and NIC, supervise EC identity and protects from premature aging.
Assuntos
Senilidade Prematura/genética , Envelhecimento/genética , Proteínas de Drosophila/genética , Drosophila melanogaster/fisiologia , Enterócitos/fisiologia , Animais , Modelos Animais de Doenças , Proteínas de Drosophila/metabolismo , Feminino , Masculino , Fenótipo , ProteomaRESUMO
Previous studies have demonstrated that the base excision repair enzyme thymine DNA glycosylase (TDG) mediates recruitment of histone acetyltransferases CREB-binding protein (CBP) and p300 to DNA, suggesting a plausible role for these factors in TDG-mediated repair. Furthermore, TDG was found to potentiate CBP/p300-dependent transcription and serve as a substrate for CBP/p300 acetylation. Here, we show that the small ubiquitin-like modifier 1 (SUMO-1) protein binding activity of TDG is essential for activation of CBP and localization to promyelocytic leukemia protein oncogenic domains (PODs). SUMO-1 binding is mediated by two distinct amino- and carboxy-terminal motifs (residues 144 to 148 and 319 to 322) that are negatively regulated by DNA binding via an amino-terminal hydrophilic region (residues 1 to 121). TDG is also posttranslationally modified by covalent conjugation of SUMO-1 (sumoylation) to lysine 341. Interestingly, we found that sumoylation of TDG blocks interaction with CBP and prevents TDG acetylation in vitro. Furthermore, sumoylation effectively abrogates intermolecular SUMO-1 binding and a sumoylation-deficient mutant accumulates in PODs, suggesting that sumoylation negatively regulates translocation to these nuclear structures. These findings suggest that TDG sumoylation promotes intramolecular interactions with amino- and carboxy-terminal SUMO-1 binding motifs that dramatically alter the biochemical properties and subcellular localization of TDG.
Assuntos
Regulação Enzimológica da Expressão Gênica , Proteínas Modificadoras Pequenas Relacionadas à Ubiquitina/fisiologia , Timina DNA Glicosilase/biossíntese , Timina DNA Glicosilase/fisiologia , Fatores de Transcrição de p300-CBP/metabolismo , Sítio Alostérico , Motivos de Aminoácidos , Sequência de Aminoácidos , Animais , Linhagem Celular Tumoral , Reparo do DNA , Humanos , Camundongos , Dados de Sequência Molecular , Estrutura Terciária de Proteína , Proteína SUMO-1 , Homologia de Sequência de Aminoácidos , Transcrição GênicaRESUMO
Nearly universal among organisms, circadian rhythms coordinate biological activity to earth's orbit around the sun. To identify factors creating this rhythm and to understand the resulting outputs, entrainment of model organisms to defined circadian time-points is required. Here we detail a procedure to entrain many Drosophila to a defined circadian rhythm. Furthermore, we detail post-entrainment steps to prepare samples for immunofluorescence, nucleic acid, or protein extraction-based analysis.
Assuntos
Ritmo Circadiano/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/patogenicidade , AnimaisRESUMO
Drosophila melanogaster possesses a complex nervous system, regulating sophisticated behavioral outputs, that serves as a powerful model for dissecting molecular mechanisms underlying neuronal function and neurodegenerative disease. Immunofluorescence techniques provide a way to visualize the spatiotemporal organization of these networks, permitting observation of their development, functional location, remodeling and, eventually, degradation. However, basic immunostaining techniques do not always result in efficient antibody penetration through the brain, and supplemental techniques to enhance permeability can compromise structural integrity, altering spatial organization. Here, slow freezing of brains is shown to facilitate antibody permeability without loss of antibody specificity or brain integrity. To demonstrate the advantages of this freezing technique, the results of two commonly used permeation methods - detergent-based and partial proteolytic digestion - are compared.
Assuntos
Encéfalo/metabolismo , Drosophila melanogaster/metabolismo , Imunofluorescência/métodos , Neurônios/metabolismo , Animais , Proteínas de Drosophila/metabolismo , Congelamento , Doenças Neurodegenerativas/metabolismoRESUMO
Atxn7, a subunit of SAGA chromatin remodeling complex, is subject to polyglutamine expansion at the amino terminus, causing spinocerebellar ataxia type 7 (SCA7), a progressive retinal and neurodegenerative disease. Within SAGA, the Atxn7 amino terminus anchors Non-stop, a deubiquitinase, to the complex. To understand the scope of Atxn7-dependent regulation of Non-stop, substrates of the deubiquitinase were sought. This revealed Non-stop, dissociated from Atxn7, interacts with Arp2/3 and WAVE regulatory complexes (WRC), which control actin cytoskeleton assembly. There, Non-stop countered polyubiquitination and proteasomal degradation of WRC subunit SCAR. Dependent on conserved WRC interacting receptor sequences (WIRS), Non-stop augmentation increased protein levels, and directed subcellular localization, of SCAR, decreasing cell area and number of protrusions. In vivo, heterozygous mutation of SCAR did not significantly rescue knockdown of Atxn7, but heterozygous mutation of Atxn7 rescued haploinsufficiency of SCAR.
Assuntos
Citoesqueleto de Actina/metabolismo , Ataxina-7/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/fisiologia , Endopeptidases/metabolismo , Proteínas dos Microfilamentos/metabolismo , Animais , Regulação da Expressão Gênica , Mapeamento de Interação de Proteínas , Mapas de Interação de ProteínasAssuntos
Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Estrogênios/metabolismo , Regulação Neoplásica da Expressão Gênica , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Fatores de Transcrição/genética , Carcinoma Hepatocelular/patologia , Progressão da Doença , Humanos , Neoplasias Hepáticas/patologia , Fatores de Transcrição/metabolismoRESUMO
Decreased expression of the USP44 deubiquitinase has been associated with global increases in H2Bub1 levels during mouse embryonic stem cell (mESC) differentiation. However, whether USP44 directly deubiquitinates histone H2B or how its activity is targeted to chromatin is not known. We identified USP44 as an integral subunit of the nuclear receptor co-repressor (N-CoR) complex. USP44 within N-CoR deubiquitinates H2B in vitro and in vivo, and ablation of USP44 impairs the repressive activity of the N-CoR complex. Chromatin immunoprecipitation (ChIP) experiments confirmed that USP44 recruitment reduces H2Bub1 levels at N-CoR target loci. Furthermore, high expression of USP44 correlates with reduced levels of H2Bub1 in the breast cancer cell line MDA-MB-231. Depletion of either USP44 or TBL1XR1 impairs the invasiveness of MDA-MB-231 cells in vitro and causes an increase of global H2Bub1 levels. Our findings indicate that USP44 contributes to N-CoR functions in regulating gene expression and is required for efficient invasiveness of triple-negative breast cancer cells.
Assuntos
Histonas/metabolismo , Correpressor 1 de Receptor Nuclear/metabolismo , Proteases Específicas de Ubiquitina/metabolismo , Ubiquitinação , Linhagem Celular Tumoral , Células HEK293 , Humanos , Invasividade Neoplásica , Proteínas Nucleares/química , Proteínas Nucleares/metabolismo , Ligação Proteica , Subunidades Proteicas/metabolismo , Receptores Citoplasmáticos e Nucleares/química , Receptores Citoplasmáticos e Nucleares/metabolismo , Proteínas Repressoras/química , Proteínas Repressoras/metabolismo , Transducina/química , Transducina/metabolismo , Ubiquitina Tiolesterase , Repetições WD40RESUMO
A large population of proliferative stem cells (neoblasts) is required for physiological tissue homeostasis and post-injury regeneration in planarians. Recent studies indicate that survival of a few neoblasts after sublethal irradiation results in the clonal expansion of the surviving stem cells and the eventual restoration of tissue homeostasis and regenerative capacity. However, the precise mechanisms regulating the population dynamics of neoblasts remain largely unknown. Here, we uncovered a central role for epidermal growth factor (EGF) signaling during in vivo neoblast expansion mediated by Smed-egfr-3 (egfr-3) and its putative ligand Smed-neuregulin-7 (nrg-7). Furthermore, the EGF receptor-3 protein localizes asymmetrically on the cytoplasmic membrane of neoblasts, and the ratio of asymmetric to symmetric cell divisions decreases significantly in egfr-3(RNAi) worms. Our results not only provide the first molecular evidence of asymmetric stem cell divisions in planarians, but also demonstrate that EGF signaling likely functions as an essential regulator of neoblast clonal expansion.
Assuntos
Fator de Crescimento Epidérmico/metabolismo , Proteínas de Helminto/genética , Planárias/citologia , Regeneração/fisiologia , Células-Tronco/citologia , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Apoptose/genética , Divisão Celular Assimétrica/genética , Proliferação de Células/genética , DNA Helicases/metabolismo , Instabilidade Genômica/genética , Proteínas de Membrana/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Interferência de RNA , RNA Interferente Pequeno/genética , Transdução de Sinais , Células-Tronco/efeitos da radiaçãoRESUMO
The SAGA complex contains two enzymatic modules, which house histone acetyltransferase (HAT) and deubiquitinase (DUB) activities. USP22 is the catalytic subunit of the DUB module, but two adaptor proteins, ATXN7L3 and ENY2, are necessary for DUB activity toward histone H2Bub1 and other substrates. ATXN7L3B shares 74% identity with the N-terminal region of ATXN7L3, but the functions of ATXN7L3B are not known. Here we report that ATXN7L3B interacts with ENY2 but not other SAGA components. Even though ATXN7L3B localizes in the cytoplasm, ATXN7L3B overexpression increases H2Bub1 levels, while overexpression of ATXN7L3 decreases H2Bub1 levels. In vitro, ATXN7L3B competes with ATXN7L3 to bind ENY2, and in vivo, knockdown of ATXN7L3B leads to concomitant loss of ENY2. Unlike the ATXN7L3 DUB complex, a USP22-ATXN7L3B-ENY2 complex cannot deubiquitinate H2Bub1 efficiently in vitro Moreover, ATXN7L3B knockdown inhibits migration of breast cancer cells in vitro and limits expression of ER target genes. Collectively, our studies suggest that ATXN7L3B regulates H2Bub1 levels and SAGA DUB activity through competition for ENY2 binding.
Assuntos
Neoplasias da Mama/metabolismo , Citoplasma/metabolismo , Histonas/metabolismo , Tioléster Hidrolases/metabolismo , Fatores de Transcrição/metabolismo , Movimento Celular , Núcleo Celular/enzimologia , Feminino , Técnicas de Silenciamento de Genes , Células HEK293 , Humanos , Células MCF-7 , Fatores de Transcrição/genética , Ubiquitina Tiolesterase , Regulação para CimaRESUMO
The SAGA chromatin modifying complex functions as a transcriptional coactivator for a large number of genes, and SAGA dysfunction has been linked to carcinogenesis and neurodegenerative disease. The protein complex is comprised of approximately 20 subunits, arranged in a modular fashion, and includes 2 enzymatic subunits: the Gcn5 acetyltransferase and the Non-stop deubiquitinase. As we learn more about SAGA, it becomes evident that this complex functions through sophisticated mechanisms that support very precise regulation of gene expression. Here we describe recent findings in which a Drosophila loss-of-function model revealed novel mechanisms for regulation of SAGA-mediated histone H2B deubiquitination. This model also yielded novel and surprising insights into mechanisms that underlie progressive neurodegenerative disease. Lastly, we comment on the utility of Drosophila as a model for neurodegenerative disease through which crucial and conserved mechanisms may be revealed.
Assuntos
Proteínas de Drosophila/metabolismo , Drosophila/metabolismo , Endopeptidases/metabolismo , Histonas/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Doenças Neurodegenerativas/etiologia , Animais , Ataxina-7 , Modelos Animais de Doenças , Feminino , Proteínas do Tecido Nervoso/genética , Doenças Neurodegenerativas/metabolismo , Degeneração Retiniana/etiologia , Degeneração Retiniana/metabolismo , Fatores de Transcrição/metabolismo , UbiquitinaçãoRESUMO
Spinocerebellar ataxia 7 (SCA7) is an incurable disease caused by expansion of CAG trinucleotide sequences within the Ataxin-7 gene. This elongated CAG tract results in an Ataxin-7 protein bearing an expanded polyglutamine (PolyQ) repeat. SCA7 disease is characterized by progressive neural and retinal degeneration leading to ataxia and blindness. Evidence gathered from investigating SCA7 and other PolyQ diseases strongly suggest that misregulation of gene expression contributes to neurodegeneration. In fact, Ataxin-7 is a subunit of the essential Spt-Ada-Gcn5-Acetltransferase (SAGA) chromatin modifying complex that regulates expression of a large number of genes. Here we discuss recent insights into Ataxin-7 function and, considering these findings, propose a model for how polyglutamine expansion of Ataxin-7 may affect Ataxin-7 function to alter chromatin modifications and gene expression.
RESUMO
Nine genetic diseases arise from expansion of CAG repeats in seemingly unrelated genes. They are referred to as polyglutamine (polyQ) diseases due to the presence of elongated glutamine tracts in the corresponding proteins. The pathologic consequences of polyQ expansion include progressive spinal, cerebellar, and neural degeneration. These pathologies are not identical, however, suggesting that disruption of protein-specific functions is crucial to establish and maintain each disease. A closer examination of protein function reveals that several act as regulators of gene expression. Here we examine the roles these proteins play in regulating gene expression, discuss how polyQ expansion may disrupt these functions to cause disease, and speculate on the neural specificity of perturbing ubiquitous gene regulators.
Assuntos
Cromatina/genética , Regulação da Expressão Gênica , Predisposição Genética para Doença/genética , Doenças Neurodegenerativas/genética , Expansão das Repetições de Trinucleotídeos/genética , Cromatina/metabolismo , Humanos , Modelos Genéticos , Doenças Neurodegenerativas/metabolismo , Peptídeos/genética , Peptídeos/metabolismo , Ligação ProteicaRESUMO
Despite ongoing research efforts and attempts to bring new drugs into trial, the prognosis for brain tumors remains poor. Patients with the most common and lethal intracranial neoplasia, glioblastoma multiforme (GBM), have an average survival of one year with combination of surgical resection, radiotherapy and temozolomide. One of the main problems in the treatment of GBM is getting drugs across the blood brain barrier (BBB) efficiently. In an attempt to solve this problem, there are ongoing experimental and clinical trials to deliver drugs within stem cells. The purpose for this method is the ease by which stem cells home to the brain. This review discusses the experimental and clinical applications of stem cells for GBM. We also discuss the different properties of stem cells. This information is important to understand why one stem cell would be advantageous over another in cell therapy. We provide an overview of the different drug delivery methods, gene-based treatments and cancer vaccines for GBM, including the stem cell subset.