scholarly journals A new kind of membrane-tethered eukaryotic transcription factor that shares an auto-proteolytic processing mechanism with bacteriophage tail-spike proteins

2013 ◽  
Vol 126 (22) ◽  
pp. 5247-5258 ◽  
Author(s):  
H. Senoo ◽  
T. Araki ◽  
M. Fukuzawa ◽  
J. G. Williams
Keyword(s):  
Transcription Factor ◽  
Proteolytic Processing ◽  
Eukaryotic Transcription ◽  
Tail Spike ◽  
Processing Mechanism ◽  
Spike Proteins

scholarly journals Involvement of the putative hematopoietic transcription factor SCL in T- cell acute lymphoblastic leukemia

Blood ◽  
1992 ◽  
Vol 79 (5) ◽  
pp. 1327-1333 ◽  
Author(s):  
PD Aplan ◽  
DP Lombardi ◽  
GH Reaman ◽  
HN Sather ◽  
GD Hammond ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Lymphoblastic Leukemia ◽  
Coding Region ◽  
Eukaryotic Transcription ◽  
Helix Loop Helix ◽  
Putative Transcription Factor ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Inappropriate Expression

Abstract The SCL gene, initially discovered at the site of a translocation breakpoint associated with the development of a stem cell leukemia, encodes a protein that contains the highly conserved basic helix-loop- helix (bHLH) motif found in a large array of eukaryotic transcription factors. Recently, we have described a nonrandom, site-specific SCL rearrangement in several T-cell acute lymphoblastic leukemia (ALL) cell lines that juxtaposes SCL with a distinct transcribed locus, SIL. The SIL/SCL rearrangement was found in leukemic blasts from 11 of 70 (16%) newly diagnosed T-cell ALL patients, a prevalence substantially higher than that of the t(11;14) translocation, which has previously been reported as the most frequent nonrandom chromosomal abnormality in T- cell ALL. We did not detect the SIL/SCL rearrangement in the leukemic blasts from 30 patients with B-cell precursor ALL, indicating that the rearrangement was specific for T-cell ALL. Analysis of RNA from these patients indicated that an SIL/SCL fusion mRNA was formed, joining SIL and SCL in a head-to-tail fashion. The fusion occurs in the 5′ untranslated region (UTR) of both genes, preserving the SCL coding region. The net result of this rearrangement is that SCL mRNA expression becomes regulated by the SIL promoter, leading to inappropriate SCL expression. The resultant inappropriate expression of this putative transcription factor may then contribute to leukemic transformation in T-cell ALL.

scholarly journals Ceapins are a new class of unfolded protein response inhibitors, selectively targeting the ATF6α branch

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Ciara M Gallagher ◽  
Carolina Garri ◽  
Erica L Cain ◽  
Kenny Kean-Hooi Ang ◽  
Christopher G Wilson ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Proteolytic Processing ◽  
Unfolded Protein ◽  
New Class ◽  
Cancer Models ◽  
Membrane Bound ◽  
The Unfolded Protein Response ◽  
Protein Response

The membrane-bound transcription factor ATF6α plays a cytoprotective role in the unfolded protein response (UPR), required for cells to survive ER stress. Activation of ATF6α promotes cell survival in cancer models. We used cell-based screens to discover and develop Ceapins, a class of pyrazole amides, that block ATF6α signaling in response to ER stress. Ceapins sensitize cells to ER stress without impacting viability of unstressed cells. Ceapins are highly specific inhibitors of ATF6α signaling, not affecting signaling through the other branches of the UPR, or proteolytic processing of its close homolog ATF6β or SREBP (a cholesterol-regulated transcription factor), both activated by the same proteases. Ceapins are first-in-class inhibitors that can be used to explore both the mechanism of activation of ATF6α and its role in pathological settings. The discovery of Ceapins now enables pharmacological modulation all three UPR branches either singly or in combination.

scholarly journals The p110 Isoform of the CDP/Cux Transcription Factor Accelerates Entry into S Phase

2006 ◽  
Vol 26 (6) ◽  
pp. 2441-2455 ◽  
Author(s):  
Laurent Sansregret ◽  
Brigitte Goulet ◽  
Ryoko Harada ◽  
Brian Wilson ◽  
Lam Leduy ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Transcription Factor ◽  
Cell Cycle Progression ◽  
S Phase ◽  
Proteolytic Processing ◽  
Experimental Conditions ◽  
Division Rate ◽  
Cycle Progression ◽  
Processing Event

ABSTRACT The CDP/Cux transcription factor was previously found to acquire distinct DNA binding and transcriptional properties following a proteolytic processing event that takes place at the G1/S transition of the cell cycle. In the present study, we have investigated the role of the CDP/Cux processed isoform, p110, in cell cycle progression. Populations of cells stably expressing p110 CDP/Cux displayed a faster division rate and reached higher saturation density than control cells carrying the empty vector. p110 CDP/Cux cells reached the next S phase faster than control cells under various experimental conditions: following cell synchronization in G0 by growth factor deprivation, synchronization in S phase by double thymidine block treatment, or enrichment in G2 by centrifugal elutriation. In each case, duration of the G1 phase was shortened by 2 to 4 h. Gene inactivation confirmed the role of CDP/Cux as an accelerator of cell cycle progression, since mouse embryo fibroblasts obtained from Cutl1z/z mutant mice displayed a longer G1 phase and proliferated more slowly than their wild-type counterparts. The delay to enter S phase persisted following immortalization by the 3T3 protocol and transformation with H-RasV12. Moreover, CDP/Cux inactivation hindered both the formation of foci on a monolayer and tumor growth in mice. At the molecular level, expression of both cyclin E2 and A2 was increased in the presence of p110 CDP/Cux and decreased in its absence. Overall, these results establish that p110 CDP/Cux functions as a cell cycle regulator that accelerates entry into S phase.

Proteolytic processing of an Arabidopsis membrane-bound NAC transcription factor is triggered by cold-induced changes in membrane fluidity

2010 ◽  
Vol 427 (3) ◽  
pp. 359-367 ◽  
Author(s):  
Pil Joon Seo ◽  
Mi Jung Kim ◽  
Jin-Su Song ◽  
Youn-Sung Kim ◽  
Hie-Joon Kim ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Protein Stability ◽  
Membrane Fluidity ◽  
Calcium Influx ◽  
Pathogen Resistance ◽  
Membrane Lipid ◽  
Proteolytic Processing ◽  
Pharmacological Agents ◽  
Proteolytic Activation ◽  
Induced Changes

Changes in membrane fluidity are the earliest cellular events that occur in plant cells upon exposure to cold. This subsequently triggers physiological processes, such as calcium influx and reorganization of actin cytoskeletons, and induces expression of cold-responsive genes. The plasma-membrane-anchored NAC (NAM/ATAF/CUC) transcription factor NTL6 is of particular interest. Cold triggers proteolytic activation of the dormant NTL6 protein, which in turn elicits pathogen-resistance responses by inducing a small group of cold-inducible PR (pathogenesis-related) genes in Arabidopsis. In the present study, we show that proteolytic processing of NTL6 is regulated by cold-induced remodelling of membrane fluidity. NTL6 processing was stimulated rapidly by cold. The protein stability of NTL6 was also enhanced by cold. The effects of cold on NTL6 processing and protein stability were significantly reduced in cold-acclimatized plants, supporting the regulation of NTL6 processing by membrane fluidity. Consistent with this, although NTL6 processing was stimulated by pharmacological agents that reduce membrane fluidity and thus mimic cold, it was inhibited when plants were treated with a 18:3 unsaturated fatty acid, linolenic acid. In addition, the pattern of NTL6 processing was changed in Arabidopsis mutants with altered membrane lipid compositions. Assays employing chemicals that inhibit activities of the proteasome and proteases showed that NTL6 processing occurs via the regulated intramembrane proteolysis mechanism. Interestingly, a metalloprotease inhibitor blocked the NTL6 processing. These observations indicate that a metalloprotease activity is responsible for NTL6 processing in response to cold-induced changes in membrane fluidity.

scholarly journals Transcriptional Regulation of BACE1, the β-Amyloid Precursor Protein β-Secretase, by Sp1

2004 ◽  
Vol 24 (2) ◽  
pp. 865-874 ◽  
Author(s):  
Michelle A. Christensen ◽  
Weihui Zhou ◽  
Hong Qing ◽  
Anna Lehman ◽  
Sjaak Philipsen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Amyloid Precursor Protein ◽  
Proteolytic Processing ◽  
Precursor Protein ◽  
Transcriptional Level ◽  
Response Element ◽  
App Processing ◽  
Transcription Factor Sp1 ◽  
Β Amyloid

ABSTRACT Proteolytic processing of the β-amyloid precursor protein (APP) at the β site is essential to generate Aβ. BACE1, the major β-secretase involved in cleaving APP, has been identified as a type 1 membrane-associated aspartyl protease. We have cloned a 2.1-kb fragment upstream of the human BACE1 gene and identified key regions necessary for promoter activity. BACE1 gene expression is controlled by a TATA-less promoter. The region of bp −619 to +46 is the minimal promoter to control the transcription of the BACE1 gene. Several putative cis-acting elements, such as a GC box, HSF-1, a PU box, AP1, AP2, and lymphokine response element, are found in the 5′ flanking region of the BACE1 gene. Transcriptional activation and gel shift assays demonstrated that the BACE1 promoter contains a functional Sp1 response element, and overexpression of the transcription factor Sp1 potentiates BACE gene expression and APP processing to generate Aβ. Furthermore, Sp1 knockout reduced BACE1 expression. These results suggest that BACE1 gene expression is tightly regulated at the transcriptional level and that the transcription factor Sp1 plays an important role in regulation of BACE1 to process APP generating Aβ in Alzheimer's disease.

scholarly journals Evidence for the Direct Involvement of the Proteasome in the Proteolytic Processing of theAspergillus nidulansZinc Finger Transcription Factor PacC

2007 ◽  
Vol 282 (48) ◽  
pp. 34735-34747 ◽  
Author(s):  
América Hervás-Aguilar ◽  
José M. Rodríguez ◽  
Joan Tilburn ◽  
Herbert N. Arst ◽  
Miguel A. Peñalva
Keyword(s):  
Transcription Factor ◽  
Proteolytic Processing ◽  
Direct Involvement

Controlled nuclear import of the transcription factor NTL6 reveals a cytoplasmic role of SnRK2.8 in the drought-stress response

2012 ◽  
Vol 448 (3) ◽  
pp. 353-363 ◽  
Author(s):  
Mi Jung Kim ◽  
Mi-Jeong Park ◽  
Pil Joon Seo ◽  
Jin-Su Song ◽  
Hie-Joon Kim ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Drought Stress ◽  
Transgenic Plants ◽  
Drought Resistance ◽  
Nuclear Import ◽  
Proteolytic Processing ◽  
Transcriptional Responses ◽  
Resistance Response ◽  
Proteolytic Activation

Controlled proteolytic activation of membrane-anchored transcription factors provides an adaptation strategy that guarantees rapid transcriptional responses to abrupt environmental stresses in both animals and plants. NTL6 is a plant-specific NAC [NAM/ATAF1/2/CUC2] transcription factor that is expressed as a dormant plasma membrane-associated form in Arabidopsis. Proteolytic processing of NTL6 is triggered by abiotic stresses and ABA (abscisic acid). In the present study, we show that NTL6 is linked directly with SnRK (Snf1-related protein kinase) 2.8-mediated signalling in inducing a drought-resistance response. SnRK2.8 phosphorylates NTL6 primarily at Thr142. NTL6 phosphorylation by SnRK2.8 is required for its nuclear import. Accordingly, a mutant NTL6 protein, in which Thr142 was mutated to an alanine, was poorly phosphorylated and failed to enter the nucleus. In accordance with the role of SnRK2.8 in drought-stress signalling, transgenic plants overproducing either NTL6 or its active form 6ΔC (35S:NTL6 and 35S:6ΔC) exhibited enhanced resistance to water-deficit conditions such as those overproducing SnRK2.8 (35S:SnRK2.8). In contrast, NTL6 RNAi (RNA interference) plants were susceptible to dehydration as observed in the SnRK2.8-deficient snrk2.8-1 mutant. Furthermore, the dehydration-resistant phenotype of 35S:NTL6 transgenic plants was compromised in 35S:NTL6 X snrk2.8-1 plants. These observations indicate that SnRK2.8-mediated protein phosphorylation, in addition to a proteolytic processing event, is important for NTL6 function in inducing a drought-resistance response.

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