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PTEN counteracts FBXL2 to promote IP3R3- and Ca2+-mediated apoptosis limiting tumour growth

Overview of attention for article published in Nature, June 2017
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About this Attention Score

  • In the top 5% of all research outputs scored by Altmetric
  • High Attention Score compared to outputs of the same age (96th percentile)
  • Average Attention Score compared to outputs of the same age and source

Mentioned by

news
5 news outlets
blogs
1 blog
twitter
80 tweeters
facebook
4 Facebook pages
wikipedia
1 Wikipedia page
reddit
1 Redditor

Citations

dimensions_citation
150 Dimensions

Readers on

mendeley
145 Mendeley
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Title
PTEN counteracts FBXL2 to promote IP3R3- and Ca2+-mediated apoptosis limiting tumour growth
Published in
Nature, June 2017
DOI 10.1038/nature22965
Pubmed ID
Authors

Shafi Kuchay, Carlotta Giorgi, Daniele Simoneschi, Julia Pagan, Sonia Missiroli, Anita Saraf, Laurence Florens, Michael P. Washburn, Ana Collazo-Lorduy, Mireia Castillo-Martin, Carlos Cordon-Cardo, Said M. Sebti, Paolo Pinton, Michele Pagano

Abstract

In response to environmental cues that promote IP3 (inositol 1,4,5-trisphosphate) generation, IP3 receptors (IP3Rs) located on the endoplasmic reticulum allow the 'quasisynaptical' feeding of calcium to the mitochondria to promote oxidative phosphorylation. However, persistent Ca(2+) release results in mitochondrial Ca(2+) overload and consequent apoptosis. Among the three mammalian IP3Rs, IP3R3 appears to be the major player in Ca(2+)-dependent apoptosis. Here we show that the F-box protein FBXL2 (the receptor subunit of one of 69 human SCF (SKP1, CUL1, F-box protein) ubiquitin ligase complexes) binds IP3R3 and targets it for ubiquitin-, p97- and proteasome-mediated degradation to limit Ca(2+) influx into mitochondria. FBXL2-knockdown cells and FBXL2-insensitive IP3R3 mutant knock-in clones display increased cytosolic Ca(2+) release from the endoplasmic reticulum and sensitization to Ca(2+)-dependent apoptotic stimuli. The phosphatase and tensin homologue (PTEN) gene is frequently mutated or lost in human tumours and syndromes that predispose individuals to cancer. We found that PTEN competes with FBXL2 for IP3R3 binding, and the FBXL2-dependent degradation of IP3R3 is accelerated in Pten(-/-) mouse embryonic fibroblasts and PTEN-null cancer cells. Reconstitution of PTEN-null cells with either wild-type PTEN or a catalytically dead mutant stabilizes IP3R3 and induces persistent Ca(2+) mobilization and apoptosis. IP3R3 and PTEN protein levels directly correlate in human prostate cancer. Both in cell culture and xenograft models, a non-degradable IP3R3 mutant sensitizes tumour cells with low or no PTEN expression to photodynamic therapy, which is based on the ability of photosensitizer drugs to cause Ca(2+)-dependent cytotoxicity after irradiation with visible light. Similarly, disruption of FBXL2 localization with GGTi-2418, a geranylgeranyl transferase inhibitor, sensitizes xenotransplanted tumours to photodynamic therapy. In summary, we identify a novel molecular mechanism that limits mitochondrial Ca(2+) overload to prevent cell death. Notably, we provide proof-of-principle that inhibiting IP3R3 degradation in PTEN-deregulated cancers represents a valid therapeutic strategy.

Twitter Demographics

The data shown below were collected from the profiles of 80 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 145 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Germany 1 <1%
Unknown 144 99%

Demographic breakdown

Readers by professional status Count As %
Student > Ph. D. Student 39 27%
Researcher 15 10%
Student > Doctoral Student 13 9%
Student > Bachelor 11 8%
Student > Master 9 6%
Other 24 17%
Unknown 34 23%
Readers by discipline Count As %
Biochemistry, Genetics and Molecular Biology 50 34%
Medicine and Dentistry 18 12%
Agricultural and Biological Sciences 16 11%
Neuroscience 6 4%
Chemistry 4 3%
Other 11 8%
Unknown 40 28%

Attention Score in Context

This research output has an Altmetric Attention Score of 89. 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 27 August 2019.
All research outputs
#334,554
of 20,131,764 outputs
Outputs from Nature
#18,151
of 85,221 outputs
Outputs of similar age
#8,673
of 285,935 outputs
Outputs of similar age from Nature
#407
of 771 outputs
Altmetric has tracked 20,131,764 research outputs across all sources so far. Compared to these this one has done particularly well and is in the 98th percentile: it's in the top 5% of all research outputs ever tracked by Altmetric.
So far Altmetric has tracked 85,221 research outputs from this source. They typically receive a lot more attention than average, with a mean Attention Score of 95.3. This one has done well, scoring higher than 78% 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 285,935 tracked outputs that were published within six weeks on either side of this one in any source. This one has done particularly well, scoring higher than 96% of its contemporaries.
We're also able to compare this research output to 771 others from the same source and published within six weeks on either side of this one. This one is in the 47th percentile – i.e., 47% of its contemporaries scored the same or lower than it.