Inhibiting MYC binding to the E-box DNA motif by ME47 decreases tumour xenograft growth

Oncogene ◽  
2017 ◽  
Vol 36 (49) ◽  
pp. 6830-6837 ◽  
Author(s):  
L C Lustig ◽  
D Dingar ◽  
W B Tu ◽  
C Lourenco ◽  
M Kalkat ◽  
...  
2017 ◽  
Vol 114 (44) ◽  
pp. E9224-E9232 ◽  
Author(s):  
Jennifer M. Gerlach ◽  
Michael Furrer ◽  
Maria Gallant ◽  
Dirk Birkel ◽  
Apoorva Baluapuri ◽  
...  

The Myc oncogene is a transcription factor with a powerful grip on cellular growth and proliferation. The physical interaction of Myc with the E-box DNA motif has been extensively characterized, but it is less clear whether this sequence-specific interaction is sufficient for Myc’s binding to its transcriptional targets. Here we identify the PAF1 complex, and specifically its component Leo1, as a factor that helps recruit Myc to target genes. Since the PAF1 complex is typically associated with active genes, this interaction with Leo1 contributes to Myc targeting to open promoters.


2021 ◽  
Author(s):  
Boris Sieber ◽  
Fangfang Lu ◽  
Stephen M Stribbling ◽  
Adam G Grieve ◽  
Anderson J Ryan ◽  
...  

Dysregulation of the ERBB/EGFR signalling pathway causes multiple types of cancer (1, 2). Accordingly, ADAM17, the primary shedding enzyme that releases and activates ERBB ligands, is tightly regulated. It has recently become clear that iRhoms, inactive members of the rhomboid-like superfamily, are regulatory cofactors for ADAM17 (3, 4). Here we show that oncogenic KRAS mutants target the cytoplasmic domain of iRhom2 to induce ADAM17-dependent shedding and the release of ERBB ligands. Activation of ERK1/2 by oncogenic KRAS induces the phosphorylation of iRhom2, recruitment of the phospho-binding 14-3-3 proteins, and consequent ADAM17-dependent shedding of ERBB ligands. In addition, cancer-associated mutations in iRhom2 act as sensitisers in this pathway by further increasing KRAS-induced shedding of ERBB ligands. This mechanism is conserved in lung cancer cells, where iRhom activity is required for tumour xenograft growth. In this context, the activity of oncogenic KRAS is modulated by the iRhom2-dependent release of ERBB ligands, thus placing iRhom2 as a central component of a positive feedback loop in lung cancer cells. Overall, the cytoplasmic domain of iRhom2 is a critical component of KRAS-induced oncogenesis of lung cancer cells. Both ADAM17 and iRhom2 have also been implicated in a wide range of other cancers (5-10), so the mechanism we have revealed may also have wider oncogenic significance.


2020 ◽  
Vol 17 (3) ◽  
pp. 355-374
Author(s):  
John D. Ayres

This article considers the working practices of British cinema's only major female film producer during the early-to-mid post-Second World War era, Betty E. Box (1915–99). Via reference to her extensive archive at the British Film Institute and the films Campbell's Kingdom (1957), The Wind Cannot Read (1958) and Hot Enough for June (1964), the article charts how Box initially envisaged multi-generational casting for roles that were eventually taken by long-term collaborator Dirk Bogarde. It considers the manner in which she approached the diplomatic complexities of location shooting, with particular focus on Ralph Thomas's military romance The Wind Cannot Read, the first British film to be shot in India for twenty years at the time of its production. The reasoning for Box's ongoing absence, as a female creative figure, from scholarship addressing British cinema, and film production more generally, will also be addressed.


Diabetes ◽  
1997 ◽  
Vol 46 (3) ◽  
pp. 354-362 ◽  
Author(s):  
K. Matsuda ◽  
E. Araki ◽  
R. Yoshimura ◽  
K. Tsuruzoe ◽  
N. Furukawa ◽  
...  

2019 ◽  
Vol 70 (19) ◽  
pp. 5355-5374 ◽  
Author(s):  
Dandan Zang ◽  
Jingxin Wang ◽  
Xin Zhang ◽  
Zhujun Liu ◽  
Yucheng Wang

Abstract Plant heat shock transcription factors (HSFs) are involved in heat and other abiotic stress responses. However, their functions in salt tolerance are little known. In this study, we characterized the function of a HSF from Arabidopsis, AtHSFA7b, in salt tolerance. AtHSFA7b is a nuclear protein with transactivation activity. ChIP-seq combined with an RNA-seq assay indicated that AtHSFA7b preferentially binds to a novel cis-acting element, termed the E-box-like motif, to regulate gene expression; it also binds to the heat shock element motif. Under salt conditions, AtHSFA7b regulates its target genes to mediate serial physiological changes, including maintaining cellular ion homeostasis, reducing water loss rate, decreasing reactive oxygen species accumulation, and adjusting osmotic potential, which ultimately leads to improved salt tolerance. Additionally, most cellulose synthase-like (CSL) and cellulose synthase (CESA) family genes were inhibited by AtHSFA7b; some of them were randomly selected for salt tolerance characterization, and they were mainly found to negatively modulate salt tolerance. By contrast, some transcription factors (TFs) were induced by AtHSFA7b; among them, we randomly identified six TFs that positively regulate salt tolerance. Thus, AtHSFA7b serves as a transactivator that positively mediates salinity tolerance mainly through binding to the E-box-like motif to regulate gene expression.


2000 ◽  
Vol 275 (50) ◽  
pp. 39801
Author(s):  
Violaine K. Harris ◽  
Christine M. Coticchia ◽  
Heinz-Joachim List ◽  
Anton Wellstein ◽  
Anna Tate Riegel

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