The E3 ubiquitin ligase human murine double minute (HDM2) is overexpressed in 40%-80% of late-stage metastatic cancers in the absence of gene amplification. Hdm2 regulates p53 stability via ubiquitination and has also been implicated in altering the sensitivity of cells to TGF-beta1. Whether TGF-beta1 signaling induces Hdm2 expression leading to HDM2-mediated destabilization of p53 has not been investigated. In this study, we report that TGF-beta1-activated SMA- and MAD3 (Smad3/4) transcription factors specifically bound to the second promoter region of HDM2, leading to increased HDM2 protein expression and destabilization of p53 in human cancer cell lines. Additionally, TGF-beta1 expression led to Smad3 activation and murine double minute 2 (Mdm2) expression in murine mammary epithelial cells during epithelial-to-mesenchymal transition (EMT). Furthermore, histological analyses of human breast cancer samples demonstrated that approximately 65% of late-stage carcinomas were positive for activated Smad3 and HDM2, indicating a strong correlation between TGF-beta1-mediated induction of HDM2 and late-stage tumor progression. Identification of Hdm2 as a downstream target of TGF-beta1 represents a critical prosurvival mechanism in cancer progression and provides another point for therapeutic intervention in late-stage cancer.
Pharmacology, Toxicology and Pharmaceutical Science
3
3%
Other
11
10%
Unknown
20
18%
Attention Score in Context
Attention Score in Context
This research output has an Altmetric Attention Score of 10. 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 09 August 2022.
All research outputs
#3,897,279
of 28,695,121 outputs
Outputs from Journal of Clinical Investigation
#4,944
of 18,505 outputs
Outputs of similar age
#19,008
of 193,886 outputs
Outputs of similar age from Journal of Clinical Investigation
#12
of 67 outputs
Altmetric has tracked 28,695,121 research outputs across all sources so far. Compared to these this one has done well and is in the 85th percentile: it's in the top 25% of all research outputs ever tracked by Altmetric.
So far Altmetric has tracked 18,505 research outputs from this source. They typically receive a lot more attention than average, with a mean Attention Score of 17.1. This one has gotten more attention than average, scoring higher than 72% 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 193,886 tracked outputs that were published within six weeks on either side of this one in any source. This one has done well, scoring higher than 89% of its contemporaries.
We're also able to compare this research output to 67 others from the same source and published within six weeks on either side of this one. This one has done well, scoring higher than 80% of its contemporaries.
