Transcription factor

About: Transcription factor is a research topic. Over the lifetime, 82881 publications have been published within this topic receiving 5400448 citations. The topic is also known as: transcription factors.

Loss of the cylindromatosis tumour suppressor inhibits apoptosis by activating NF-κB

Abstract: Protein modification by the conjugation of ubiquitin moieties—ubiquitination—plays a major part in many biological processes, including cell cycle and apoptosis1. The enzymes that mediate ubiquitin-conjugation have been well-studied, but much less is known about the ubiquitin-specific proteases that mediate de-ubiquitination of cellular substrates2,3. To study this gene family, we designed a collection of RNA interference vectors to suppress 50 human de-ubiquitinating enzymes, and used these vectors to identify de-ubiquitinating enzymes in cancer-relevant pathways. We report here that inhibition of one of these enzymes, the familial cylindromatosis tumour suppressor gene (CYLD)4, having no known function, enhances activation of the transcription factor NF-κB. We show that CYLD binds to the NEMO (also known as IKKγ) component of the IκB kinase (IKK) complex, and appears to regulate its activity through de-ubiquitination of TRAF2, as TRAF2 ubiquitination can be modulated by CYLD. Inhibition of CYLD increases resistance to apoptosis, suggesting a mechanism through which loss of CYLD contributes to oncogenesis. We show that this effect can be relieved by aspirin derivatives that inhibit NF-κB activity5, which suggests a therapeutic intervention strategy to restore growth control in patients suffering from familial cylindromatosis.

TAZ, a transcriptional modulator of mesenchymal stem cell differentiation.

Abstract: Mesenchymal stem cells (MSCs) are a pluripotent cell type that can differentiate into several distinct lineages. Two key transcription factors, Runx2 and peroxisome proliferator-activated receptor gamma (PPARgamma), drive MSCs to differentiate into either osteoblasts or adipocytes, respectively. How these two transcription factors are regulated in order to specify these alternate cell fates remains a pivotal question. Here we report that a 14-3-3-binding protein, TAZ (transcriptional coactivator with PDZ-binding motif), coactivates Runx2-dependent gene transcription while repressing PPARgamma-dependent gene transcription. By modulating TAZ expression in model cell lines, mouse embryonic fibroblasts, and primary MSCs in culture and in zebrafish in vivo, we observed alterations in osteogenic versus adipogenic potential. These results indicate that TAZ functions as a molecular rheostat that modulates MSC differentiation.

Absence of granulocyte colony-stimulating factor signaling and neutrophil development in CCAAT enhancer binding protein α-deficient mice

Abstract: Transcription factors are master regulatory switches of differentiation, including the development of specific hematopoietic lineages from stem cells. Here we show that mice with targeted disruption of the CCAAT enhancer binding protein α gene (C/EBPα) demonstrate a selective block in differentiation of neutrophils. Mature neutrophils and eosinophils are not observed in the blood or fetal liver of mutant animals, while other hematopoietic lineages, including monocytes, are not affected. Instead, most of the white cells in the peripheral blood of mutant mice had the appearance of myeloid blasts. We also observed a selective loss of expression of a critical gene target of CCAAT enhancer binding protein α, the granulocyte colony-stimulating factor receptor. As a result, multipotential myeloid progenitors from the mutant fetal liver are unable to respond to granulocyte colony-stimulating factor signaling, although they are capable of forming granulocyte–macrophage and macrophage colonies in methylcellulose in response to other growth factors. Finally, we demonstrate that the lack of granulocyte development results from a defect intrinsic to the hematopoietic system; transplanted fetal liver from mutant mice can reconstitute lymphoid but not neutrophilic cells in irradiated recipients. These studies suggest a model by which transcription factors can direct the differentiation of multipotential precursors through activation of expression of a specific growth factor receptor, allowing proliferation and differentiation in response to a specific extracellular signal. In addition, the c/ebpα−/− mice may be useful in understanding the mechanisms involved in acute myelogenous leukemia, in which a block in differentiation of myeloid precursors is a key feature of the disease.

The INK4a / ARF network in tumour suppression

Abstract: The retinoblastoma protein (RB) and p53 transcription factor are regulated by two distinct proteins that are encoded by the INK4a/ARF locus. Genes encoding these four tumour suppressors are disabled, either in whole or in part, in most human cancers. A complex signalling network that interconnects the activities of RB and p53 monitors oncogenic stimuli to provide a cell-autonomous mode of tumour surveillance.

Mechanistic Studies of the Nrf2-Keap1 Signaling Pathway

Abstract: Since eukaryotic cells constantly encounter various environmental insults, they have evolved defense mechanisms to cope with toxicant- and carcinogen-induced oxidative stress or electrophiles. One of the most important cellular defense mechanisms against oxidative stress or electrophiles is mediated by the transcription factor Nrf2. Under the basal condition, Nrf2-dependent transcription is repressed by a negative regulator Keap1. When cells are exposed to oxidative stress, electrophiles, or chemopreventive agents, Nrf2 escapes Keap1-mediated repression and activates antioxidant responsive element (ARE)-dependent gene expression to maintain cellular redox homeostasis. Beyond its antioxidant function, Nrf2 has recently been recognized as a key factor regulating an array of genes that defend cells against the deleterious effects of environmental insults. Since this Nrf2-dependent cellular defense response is able to protect multi-organs or multi-tissues, activation of Nrf2 has been implicated in conferring ...