Year: 2015
Type: article
Abstract: The promyelocytic leukemia (PML) protein is a tumor suppressor originally identified in acute promyelocytic leukemia and implicated in tumorigenesis in multiple forms of cancer. PML protein is frequently down-regulated in various cancers, but PML mRNA levels are relatively similar between normal and cancerous tissues (1). These observations indicate that PML protein levels are tightly regulated, in part, through post-transcriptional modification. We previously demonstrated that the PML protein undergoes ubiquitination (Ub)-mediated degradation facilitated by an E3 ligase UHRF1 (2), and that SIRT1/SIRT5 promotes deacetylation and SUMO1 conjugation of PML (3) in response to oxidative stress. Here, we found that the small noncoding RNA miR-24 and miR-133 target 3′ UTR of PML1 mRNA, the major PML isoform in primary human endothelial cells (ECs). In normal culture condition, miR-24 and miR-133 down-regulate PML1 protein expression in primary human ECs. However, miR-24 but not miR-133 up-regulates PML1 protein expression under starvation condition. Moreover, miR-24 inhibits ECs angiogenesis, while knocking down PML attenuates the inhibitory effect of miR-24 to angiogenesis. We confirm miR-24 inhibitory effect on angiogenesis ex-vivo. miR-24 inhibits angiogenesis of PML wild-type but not PML-/- mouse aortic ECs as demonstrated by aorta ring assays. These findings revealed a new mechanism that miR-24 switches from an inhibitor to an activator if PML1 mRNA translation under serum starvation condition Funding: NIH R01 DK078965 & HL093269.
Source: The FASEB Journal
Institution: Case Western Reserve University
Language: English
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W1534943207