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Distinct inhibitory effects on mTOR signaling by ethanol and INK128 in diffuse large B-cell lymphoma

Overview of attention for article published in Cell Communication and Signaling, January 2015
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2 tweeters

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Title
Distinct inhibitory effects on mTOR signaling by ethanol and INK128 in diffuse large B-cell lymphoma
Published in
Cell Communication and Signaling, January 2015
DOI 10.1186/s12964-015-0091-0
Pubmed ID
Authors

Krystyna Mazan-Mamczarz, Raymond J Peroutka, James J Steinhardt, Moriah Gidoni, Yongqing Zhang, Elin Lehrmann, Ari L Landon, Bojie Dai, Simone Houng, Parameswary A Muniandy, Sol Efroni, Kevin G Becker, Ronald B Gartenhaus

Abstract

The mechanistic target of rapamycin, (mTOR) kinase plays a pivotal role in controlling critical cellular growth and survival pathways, and its aberrant induction is implicated in cancer pathogenesis. Therefore, suppression of active mTOR signaling has been of great interest to researchers; several mTOR inhibitors have been discovered to date. Ethanol (EtOH), similar to pharmacologic mTOR inhibitors, has been shown to suppress the mTOR signaling pathway, though in a non-catalytic manner. Despite population studies showing that the consumption of EtOH has a protective effect against hematological malignancies, the mechanisms behind EtOH's modulation of mTOR activity in cells and its downstream consequences are largely unknown. Here we evaluated the effects of EtOH on the mTOR pathway, in comparison to the active-site mTOR inhibitor INK128, and compared translatome analysis of their downstream effects in diffuse large B-cell lymphoma (DLBCL). Treatment of DLBCL cells with EtOH suppressed mTORC1 complex formation while increasing AKT phosphorylation and mTORC2 complex assembly. INK128 completely abrogated AKT phosphorylation without affecting the structure of mTORC1/2 complexes. Accordingly, EtOH less profoundly suppressed cap-dependent translation and global protein synthesis, compared to a remarkable inhibitory effect of INK128 treatment. Importantly, EtOH treatment induced the formation of stress granules, while INK128 suppressed their formation. Microarray analysis of polysomal RNA revealed that although both agents primarily affected cell growth and survival, EtOH and INK128 regulated the synthesis of mostly distinct genes involved in these processes. Though both EtOH and INK128 inhibited cell cycle, proliferation and autophagy, EtOH, in contrast to INK128, did not induce cell apoptosis. Given that EtOH, similar to pharmacologic mTOR inhibitors, inhibits mTOR signaling, we systematically explored the effect of EtOH and INK128 on mTOR signal transduction, components of the mTORC1/2 interaction and their downstream effectors in DLBCL malignancy. We found that EtOH partially inhibits mTOR signaling and protein translation, compared to INK128's complete mTOR inhibition. Translatome analysis of mTOR downstream target genes established that differential inhibition of mTOR by EtOH and INK128 distinctly modulates translation of specific subsets of mRNAs involved in cell growth and survival, leading to differential cellular response and survival.

Twitter Demographics

The data shown below were collected from the profiles of 2 tweeters who shared this research output. Click here to find out more about how the information was compiled.

Mendeley readers

The data shown below were compiled from readership statistics for 18 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Japan 1 6%
United Kingdom 1 6%
Unknown 16 89%

Demographic breakdown

Readers by professional status Count As %
Researcher 5 28%
Student > Ph. D. Student 3 17%
Student > Bachelor 2 11%
Student > Master 2 11%
Other 1 6%
Other 2 11%
Unknown 3 17%
Readers by discipline Count As %
Agricultural and Biological Sciences 6 33%
Medicine and Dentistry 4 22%
Biochemistry, Genetics and Molecular Biology 3 17%
Neuroscience 1 6%
Unknown 4 22%

Attention Score in Context

This research output has an Altmetric Attention Score of 2. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 02 February 2018.
All research outputs
#7,508,183
of 12,452,101 outputs
Outputs from Cell Communication and Signaling
#118
of 300 outputs
Outputs of similar age
#113,541
of 229,500 outputs
Outputs of similar age from Cell Communication and Signaling
#3
of 7 outputs
Altmetric has tracked 12,452,101 research outputs across all sources so far. This one is in the 37th percentile – i.e., 37% of other outputs scored the same or lower than it.
So far Altmetric has tracked 300 research outputs from this source. They receive a mean Attention Score of 3.0. This one has gotten more attention than average, scoring higher than 56% of its peers.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 229,500 tracked outputs that were published within six weeks on either side of this one in any source. This one is in the 46th percentile – i.e., 46% of its contemporaries scored the same or lower than it.
We're also able to compare this research output to 7 others from the same source and published within six weeks on either side of this one. This one has scored higher than 4 of them.