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Antisense oligonucleotide–mediated MDM4 exon 6 skipping impairs tumor growth

Overview of attention for article published in Journal of Clinical Investigation, November 2015
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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 (97th percentile)
  • High Attention Score compared to outputs of the same age and source (92nd percentile)

Mentioned by

news
7 news outlets
blogs
2 blogs
twitter
4 X users
patent
3 patents

Citations

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142 Dimensions

Readers on

mendeley
138 Mendeley
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Title
Antisense oligonucleotide–mediated MDM4 exon 6 skipping impairs tumor growth
Published in
Journal of Clinical Investigation, November 2015
DOI 10.1172/jci82534
Pubmed ID
Authors

Michael Dewaele, Tommaso Tabaglio, Karen Willekens, Marco Bezzi, Shun Xie Teo, Diana H.P. Low, Cheryl M. Koh, Florian Rambow, Mark Fiers, Aljosja Rogiers, Enrico Radaelli, Muthafar Al-Haddawi, Soo Yong Tan, Els Hermans, Frederic Amant, Hualong Yan, Manikandan Lakshmanan, Ratnacaram Chandrahas Koumar, Soon Thye Lim, Frederick A. Derheimer, Robert M. Campbell, Zahid Bonday, Vinay Tergaonkar, Mark Shackleton, Christine Blattner, Jean-Christophe Marine, Ernesto Guccione

Abstract

MDM4 is a promising target for cancer therapy, as it is undetectable in most normal adult tissues but often upregulated in cancer cells to dampen p53 tumor-suppressor function. The mechanisms that underlie MDM4 upregulation in cancer cells are largely unknown. Here, we have shown that this key oncogenic event mainly depends on a specific alternative splicing switch. We determined that while a nonsense-mediated, decay-targeted isoform of MDM4 (MDM4-S) is produced in normal adult tissues as a result of exon 6 skipping, enhanced exon 6 inclusion leads to expression of full-length MDM4 in a large number of human cancers. Although this alternative splicing event is likely regulated by multiple splicing factors, we identified the SRSF3 oncoprotein as a key enhancer of exon 6 inclusion. In multiple human melanoma cell lines and in melanoma patient-derived xenograft (PDX) mouse models, antisense oligonucleotide-mediated (ASO-mediated) skipping of exon 6 decreased MDM4 abundance, inhibited melanoma growth, and enhanced sensitivity to MAPK-targeting therapeutics. Additionally, ASO-based MDM4 targeting reduced diffuse large B cell lymphoma PDX growth. As full-length MDM4 is enhanced in multiple human tumors, our data indicate that this strategy is applicable to a wide range of tumor types. We conclude that enhanced MDM4 exon 6 inclusion is a common oncogenic event and has potential as a clinically compatible therapeutic target.

X Demographics

X Demographics

The data shown below were collected from the profiles of 4 X users who shared this research output. Click here to find out more about how the information was compiled.
Mendeley readers

Mendeley readers

The data shown below were compiled from readership statistics for 138 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
United Kingdom 1 <1%
Denmark 1 <1%
Unknown 136 99%

Demographic breakdown

Readers by professional status Count As %
Student > Ph. D. Student 29 21%
Researcher 26 19%
Student > Master 16 12%
Student > Bachelor 11 8%
Other 6 4%
Other 24 17%
Unknown 26 19%
Readers by discipline Count As %
Biochemistry, Genetics and Molecular Biology 47 34%
Agricultural and Biological Sciences 35 25%
Medicine and Dentistry 9 7%
Immunology and Microbiology 3 2%
Chemistry 3 2%
Other 8 6%
Unknown 33 24%
Attention Score in Context

Attention Score in Context

This research output has an Altmetric Attention Score of 73. 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 17 January 2023.
All research outputs
#576,117
of 25,186,033 outputs
Outputs from Journal of Clinical Investigation
#645
of 17,110 outputs
Outputs of similar age
#9,506
of 398,650 outputs
Outputs of similar age from Journal of Clinical Investigation
#9
of 102 outputs
Altmetric has tracked 25,186,033 research outputs across all sources so far. Compared to these this one has done particularly well and is in the 97th percentile: it's in the top 5% of all research outputs ever tracked by Altmetric.
So far Altmetric has tracked 17,110 research outputs from this source. They typically receive a lot more attention than average, with a mean Attention Score of 16.6. This one has done particularly well, scoring higher than 96% 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 398,650 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 97% of its contemporaries.
We're also able to compare this research output to 102 others from the same source and published within six weeks on either side of this one. This one has done particularly well, scoring higher than 92% of its contemporaries.