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1.
Mol Immunol ; 116: 174-179, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31704500

RESUMO

We considered the possibility that the greater the distance between an immune receptor V and J, the more likely the V usage. Such a hypothesis is supported by results from mouse experiments. And, such a hypothesis is consistent with the fundamental nature of recombination and genomic distance: the further the distance, the greater the chance of a DNA break. Thus, we exploited the vast dataset of V and J recombination reads available for the human TRA gene, particularly from cancer and blood specimens, to assess the frequency of TRAV usage with respect to distance from the TRAJ cluster. Results indicated that, indeed, over the entire TRAV cluster, there is a greater chance of V usage the further the distance from the J cluster. These results do not address causation, and are not consistent for certain individual V gene segments, but the results do indicate that overall, the larger the distance between the V and J gene segment cluster, the more likely the appearance of at least a subset of TRAV segments, particularly among tumor infiltrating lymphocytes. With a similar approach, the distal TRAV gene segments were also found to be more commonly associated with a subset of distal TRAJ segments. These results have implications for restrictions on the apparent TRA repertoire in disease settings.


Assuntos
Família Multigênica/genética , Neoplasias/genética , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Humanos , Linfócitos do Interstício Tumoral/imunologia , Família Multigênica/imunologia , Neoplasias/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia
3.
Hum Vaccin Immunother ; 12(3): 593-8, 2016 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-26453454

RESUMO

HLA-DR is the most commonly expressed and likely the most medically important human MHC class II, antigen presenting protein. In a normal immune response, HLA-DR binds to antigenic peptide and the HLA-DR/peptide complex binds to a T-cell receptor, thus contributing to T-cell activation and stimulation of an immune response against the antigen. When foreign antigen is not present, HLA-DR binds endogenous peptide which, under normal conditions does not stimulate an immune response. In most cases, the human peptide is CLIP, but a certain percentage of HLA-DR molecules will be present at the cell surface with other human peptides. We have recently shown that cell surface, CLIP/HLA-DR ratios are a measure of peptide heterogeneity, and in particular, changes in CLIP/HLA-DR ratios represent changes in the occupancy of HLA-DR by other, endogenous peptides. For example, treatment of cells with the HDAC inhibitor, Entinostat, leads to an upregulation of Cathepsin L1 and replacement of Cathepsin L1 senstitive peptides with HLA-DR binding, Cathepsin L1 resistant peptides, an alteration that can be at least partially assessed via assessment of CLIP/HLA-DR cell surface ratios. Here we assay for CLIP/HLA-DR ratios following treatment of immortalized B-cells with a variety of common drugs, almost all of which indicate significant changes in the CLIP/HLA-DR ratios. Furthermore, the CLIP/HLA-DR ratio changes parallel the impact of the drug panoply on cell viability, suggesting that alterations in the HLA-DR peptidome are governed by a variety of mechanisms, rather than exclusively dependent on a dedicated peptide loading process. These results raise questions about how FDA approved drugs may affect the immune response, and whether any of these drugs could be useful as vaccine adjuvants?


Assuntos
Apresentação de Antígeno/efeitos dos fármacos , Antígenos de Diferenciação de Linfócitos B/análise , Linfócitos B/química , Linfócitos B/efeitos dos fármacos , Antígenos HLA-DR/análise , Antígenos de Histocompatibilidade Classe II/análise , Humanos
4.
Cell Cycle ; 14(15): 2494-500, 2015 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-25945879

RESUMO

Apoptosis- and proliferation-effector genes are substantially regulated by the same transactivators, with E2F-1 and Oct-1 being notable examples. The larger proliferation-effector genes have more binding sites for the transactivators that regulate both sets of genes, and proliferation-effector genes have more regions of active chromatin, i.e, DNase I hypersensitive and histone 3, lysine-4 trimethylation sites. Thus, the size differences between the 2 classes of genes suggest a transcriptional regulation paradigm whereby the accumulation of transcription factors that regulate both sets of genes, merely as an aspect of stochastic behavior, accumulate first on the larger proliferation-effector gene "traps," and then accumulate on the apoptosis effector genes, thereby effecting sequential activation of the 2 different gene sets. As IRF-1 and p53 levels increase, tumor suppressor proteins are first activated, followed by the activation of apoptosis-effector genes, for example during S-phase pausing for DNA repair. Tumor suppressor genes are larger than apoptosis-effector genes and have more IRF-1 and p53 binding sites, thereby likewise suggesting a paradigm for transcription sequencing based on stochastic interactions of transcription factors with different gene classes. In this report, using the ENCODE database, we determined that tumor suppressor genes have a greater number of open chromatin regions and histone 3 lysine-4 trimethylation sites, consistent with the idea that a larger gene size can facilitate earlier transcriptional activation via the inclusion of more transactivator binding sites.


Assuntos
Apoptose/genética , Regulação da Expressão Gênica/genética , Genes Supressores de Tumor , Elementos Reguladores de Transcrição/genética , Ativação Transcricional/genética , Sítios de Ligação/genética , Cromatina/metabolismo , Metilação de DNA/genética , Proteínas de Ligação a DNA/metabolismo , Fator de Transcrição E2F1/genética , Humanos , Transportador 1 de Cátions Orgânicos/genética
5.
Gene ; 554(1): 50-7, 2015 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-25307873

RESUMO

Cancer cells undergo a variety of DNA copy number gains and losses (CNV), raising two important questions related to cancer development: (i) Which genes are affected? (ii) And how do CNVs, that do not represent complete deletions but do represent gene-dosage alterations, impact cancer cell functions? Recent studies have indicated that CNVs in cancer can impact genes for regulatory proteins long known to be associated with cancer development, but less is understood about CNVs affecting effector genes. Also, we have recently indicated the likely importance of transcription factor binding site (TFBS) copies in effector genes, in regulating the transition from a proliferative to an apoptotic state. Here we report data-mining analyses that indicate that copies of apoptosis-effector genes are commonly lost in cancer development, in comparison to proliferation-effector genes, and when not, apoptosis effector genes have silenced chromatin structures.


Assuntos
Apoptose , Variações do Número de Cópias de DNA , Dosagem de Genes , Regulação Neoplásica da Expressão Gênica , Inativação Gênica , Neoplasias/genética , Proliferação de Células , Cromatina/metabolismo , Biologia Computacional , Mineração de Dados , Genoma Humano , Humanos , Mutação , Fatores de Transcrição/metabolismo , Proteína Supressora de Tumor p53/metabolismo
6.
Cancer Lett ; 356(2 Pt B): 479-82, 2015 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-25451318

RESUMO

We determined the most commonly mutated genes in five cancer genome atlas (TCGA) datasets. Many of these genes were extraordinarily large, as are many cancer fusion gene partners. And many of these genes had cytoskeletal related functions. We further determined that these genes were distributed into high and low frequency mutation groups largely according to overall rate of gene-occurrence in the high and low mutation frequency groups, as was also the case with common metastasis and tumor suppressor genes. Oncoproteins were selectively mutated in the low mutation frequency groups in colon and lung datasets. Thus, genes that have very large coding regions and may impact the cytoskeleton are more commonly mutated than are common metastasis and tumor suppressor genes in both high and low frequency mutation groups. These analyses raise questions related to cell shape: (i) Are cancer cells often spherical because cytoskeletal-related proteins are large mutagen targets? (ii) Is drug-resistance facilitated by relatively common mutant proteins that lead to round cells, with altered cell physiology or reduced surface to volume ratios that could reduce intra-cellular drug concentrations?


Assuntos
Forma Celular/genética , Resistencia a Medicamentos Antineoplásicos/genética , Genes Supressores de Tumor , Mutagênicos/efeitos adversos , Mutação/genética , Neoplasias/genética , Oncogenes/genética , Antineoplásicos/farmacologia , Forma Celular/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Genoma Humano/genética , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/patologia
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