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1.
PLoS One ; 10(7): e0132856, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26177549

RESUMO

Much progress has been made in understanding the important cis-mediated controls on mouse TCRα gene function, including identification of the Eα enhancer and TCRα locus control region (LCR). Nevertheless, previous data have suggested that other cis-regulatory elements may reside in the locus outside of the Eα/LCR. Based on prior findings, we hypothesized the existence of gene regulatory elements in a 3.9-kb region 5' of the Cα exons. Using DNase hypersensitivity assays and TCRα BAC reporter transgenes in mice, we detected gene regulatory activity within this 3.9-kb region. This region is active in both thymic and peripheral T cells, and selectively affects upstream, but not downstream, gene expression. Together, these data indicate the existence of a novel cis-acting regulatory complex that contributes to TCRα transgene expression in vivo. The active chromatin sites we discovered within this region would remain in the locus after TCRα gene rearrangement, and thus may contribute to endogenous TCRα gene activity, particularly in peripheral T cells, where the Eα element has been found to be inactive.


Assuntos
Regulação da Expressão Gênica , Loci Gênicos , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Linfócitos T/citologia , Timo/citologia , Animais , Cromatina/genética , Desoxirribonuclease I/metabolismo , Genes Reporter , Humanos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Deleção de Sequência , Linfócitos T/metabolismo
2.
Dev Genes Evol ; 207(2): 127-130, 1997 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27747405

RESUMO

We have isolated the Drosophila gene skittles (sktl) which shows homology to members of a novel family of phosphatidylinositol-4-phosphate 5-kinases, including the gene product encoded by the human STM-7.I gene which has been assigned to the neurodegenerative disorder Friedreichs ataxia. In situ hybridization reveals sktl expression during oogenesis and spermatogenesis.

3.
PLoS One ; 5(11): e15527, 2010 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-21124935

RESUMO

The molecular mechanisms regulating the activity of the TCRα gene are required for the production of the circulating T cell repertoire. Elements of the mouse TCRα locus control region (LCR) play a role in these processes. We previously reported that TCRα LCR DNA supports a gene expression pattern that mimics proper thymus-stage, TCRα gene-like developmental regulation. It also produces transcription of linked reporter genes in peripheral T cells. However, TCRα LCR-driven transgenes display ectopic transcription in B cells in multiple reporter gene systems. The reasons for this important deviation from the normal TCRα gene regulation pattern are unclear. In its natural locus, two genes flank the TCRα LCR, TCRα (upstream) and Dad1 (downstream). We investigated the significance of this gene arrangement to TCRα LCR activity by examining transgenic mice bearing a construct where the LCR was flanked by two separate reporter genes. Surprisingly, the presence of a second, distinct, reporter gene downstream of the LCR virtually eliminated the ectopic B cell expression of the upstream reporter observed in earlier studies. Downstream reporter gene activity was unaffected by the presence of a second gene upstream of the LCR. Our findings indicate that a gene arrangement in which the TCRα LCR is flanked by two distinct transcription units helps to restrict its activity, selectively, on its 5'-flanking gene, the natural TCRα gene position with respect to the LCR. Consistent with these findings, a TCRα/Dad1 locus bacterial artificial chromosome dual-reporter construct did not display the ectopic upstream (TCRα) reporter expression in B cells previously reported for single TCRα transgenes.


Assuntos
Linfócitos B/metabolismo , Regulação da Expressão Gênica , Região de Controle de Locus Gênico/genética , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Animais , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Antígenos CD2/genética , Antígenos CD2/metabolismo , Citometria de Fluxo , Antígeno HLA-B7/genética , Antígeno HLA-B7/metabolismo , Histonas/metabolismo , Humanos , Tecido Linfoide/metabolismo , Lisina/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Metilação , Camundongos , Camundongos Transgênicos , Regiões Promotoras Genéticas/genética , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Baço/metabolismo , Timo/citologia , Timo/metabolismo
4.
J Biol Chem ; 280(43): 35829-35, 2005 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-16109716

RESUMO

A critical aspect of tumor progression is the generation of survival signals that overcome default apoptotic programs. Recent studies have revealed that elevated phospholipase D activity generates survival signals in breast and perhaps other human cancers. We report here that the elevated phospholipase D activity in the human breast cancer cell line MDA-MB-231 suppresses the activity of the putative tumor suppressor protein phosphatase 2A in a mammalian target of rapamycin (mTOR)-dependent manner. Increasing the phospholipase D activity in MCF7 cells also suppressed protein phosphatase 2A activity. Elevated phospholipase D activity suppressed association of protein phosphatase 2A with both ribosomal subunit S6-kinase and eukaryotic initiation factor 4E-binding protein 1. Suppression of protein phosphatase 2A by SV40 small t-antigen has been reported to be critical for the transformation of human cells with SV40 early region genes. Consistent with a critical role for protein phosphatase 2A in phospholipase D survival signals, either SV40 small t-antigen or pharmacological suppression of protein phosphatase 2A restored survival signals lost by the suppression of either phospholipase D or mTOR. Blocking phospholipase D signals also led to reduced phosphorylation of the pro-apoptotic protein BAD at the protein phosphatase 2A dephosphorylation site at Ser-112. The ability of phospholipase D to suppress protein phosphatase 2A identifies a critical target of an emerging phospholipase D/mTOR survival pathway in the transformation of human cells.


Assuntos
Neoplasias da Mama/patologia , Fosfolipase D/metabolismo , Fosfoproteínas Fosfatases/antagonistas & inibidores , Proteínas Quinases/fisiologia , Proteínas Adaptadoras de Transdução de Sinal , Antígenos Transformantes de Poliomavirus/metabolismo , Apoptose , Western Blotting , Proteínas de Transporte/metabolismo , Proteínas de Ciclo Celular , Linhagem Celular Tumoral , Sobrevivência Celular , Humanos , Imunoprecipitação , Modelos Biológicos , Mutação , Fosfolipase D/química , Fosfoproteínas/metabolismo , Fosforilação , Proteínas Quinases/metabolismo , Proteína Fosfatase 2 , RNA Interferente Pequeno/metabolismo , Proteínas Quinases S6 Ribossômicas/metabolismo , Ribossomos/enzimologia , Serina/química , Serina-Treonina Quinases TOR
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