The MicroRNA 15a/16–1 Cluster Down-regulates Protein Repair Isoaspartyl Methyltransferase in Hepatoma Cells

Sambri, Irene; Capasso, Rosanna; Pucci, Piero; Perna, Alessandra F.; Ingrosso, Diego

doi:10.1074/jbc.m111.290437

Cited by 17 publications

(9 citation statements)

References 41 publications

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“…These data suggest that the increased expression of PIMT might be a key genetic event during cancer development. On the basis of these findings and previous observations16171819, we hypothesized that PIMT could be involved in regulating the function of p53, which is a potent tumour suppressor and major regulator of apoptosis. To test this hypothesis, we examined the expression levels of PIMT and p53 in several cell lines.…”

Section: Resultsmentioning

confidence: 70%

“…S11a–d). Several studies demonstrate that the deamidation rate could also be regulated through signal-transduction pathways: the deamidation of Bcl-xL occurs in response to DNA damage121314151619 and is suppressed by the Rb protein12, the p56 lck kinase14, the BCR-ABL and mutant JAK2 proteins15. Thus, we speculate that there is a specific regulation mechanism for accelerating the asparagine deamidation of p53 in the intracellular environment, even though asparagine residues 29 and 30 of short-lived p53 are present in an unusual deamidation-susceptible sequence.…”

Section: Discussionmentioning

confidence: 99%

“…These studies show that the induction of PIMT protects cells from apoptosis caused by H 2 O 2 stress16 or Bax overexpression17, whereas the inhibition of PIMT increases apoptosis upon DNA damage18. In addition, the effect of PIMT on apoptosis is mediated through modulating the deamidation of Bcl-xL1619. Although these results raise the possibility that PIMT could be a regulator of apoptosis, the precise molecular mechanisms of PIMT in apoptosis have yet to be defined.…”

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confidence: 99%

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Protein L-isoaspartyl methyltransferase regulates p53 activity

et al. 2012

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Protein methylation plays important roles in most, if not all, cellular processes. Lysine and arginine methyltransferases are known to regulate the function of histones and non-histone proteins through the methylation of specific sites. However, the role of the carboxyl-methyltransferase protein L-isoaspartyl methyltransferase (PIMT) in the regulation of protein functions is relatively less understood. Here we show that PIMT negatively regulates the tumour suppressor protein p53 by reducing p53 protein levels, thereby suppressing the p53-mediated transcription of target genes. In addition, PIMT depletion upregulates the proapoptotic and checkpoint activation functions of p53. Moreover, PIMT destabilizes p53 by enhancing the p53–HDM2 interaction. These PIMT effects on p53 stability and activity are attributed to the PIMT-mediated methylation of p53 at isoaspartate residues 29 and 30. Our study provides new insight into the molecular mechanisms by which PIMT suppresses the p53 activity through carboxyl methylation, and suggests a therapeutic target for cancers.

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Section: Resultsmentioning

confidence: 70%

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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Protein L-isoaspartyl methyltransferase regulates p53 activity

et al. 2012

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“…Additionally this model implicates PCMT1 and isoaspartyl residues as age-related switches regulating entry into apoptotic pathways as has recently been shown in BCL-xL [45] [44] and p53 [46]. Additionally, wortmannin itself has been shown to trigger apoptosis through inhibition of PI3K class kinases [55]–[56] in a manner somewhat opposite of Pcmt1.…”

Section: Discussionmentioning

confidence: 81%

Wortmannin Reduces Insulin Signaling and Death in Seizure-Prone Pcmt1−/− Mice

2012

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L-isoaspartyl (D-aspartyl) O-methyltransferase deficient mice (Pcmt1−/−) accumulate isomerized aspartyl residues in intracellular proteins until their death due to seizures at approximately 45 days. Previous studies have shown that these mice have constitutively activated insulin signaling in their brains, and that these brains are 20–30% larger than those from age-matched wild-type animals. To determine whether insulin pathway activation and brain enlargement is responsible for the fatal seizures, we administered wortmannin, an inhibitor of the phosphoinositide 3-kinase that catalyzes an early step in the insulin pathway. Oral wortmannin reduced the average brain size in the Pcmt1−/− animals to within 6% of the wild-type DMSO administered controls, and nearly doubled the lifespan of Pcmt1−/− at 60% survival of the original population. Immunoblotting revealed significant decreases in phosphorylation of Akt, PDK1, and mTOR in Pcmt1−/− mice and Akt and PDK1 in wild-type animals upon treatment with wortmannin. These data suggest activation of the insulin pathway and its resulting brain enlargement contributes to the early death of Pcmt1−/− mice, but is not solely responsible for the early death observed in these animals.

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“…Interestingly, miR-15a, -15b and -16 are known as tumor-suppressor miRNAs as their activity directly represses the expression of anti-apoptotic genes such as Bcl2 (validated in human, mouse and rat 23 24 ), Ccnd1 (validated in human, mouse and rat 25 ) and protein carboxyl-O-methyltransferase (Pcmt1; validated in human 26 ). Mcl1 is indicated in the literature as validated miR-15a target in humans, however to the best of our knowledge, this interaction has never been experimentally validated and, for the purpose of this study, Mcl1 is included as miR-15a predicted target 27 .…”

Section: Resultsmentioning

confidence: 99%

Hyperosmotic stress activates the expression of members of the miR-15/107 family and induces downregulation of anti-apoptotic genes in rat liver

Santosa

Castoldi

Paluschinski

et al. 2015

Sci Rep

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microRNAs are an abundant class of small non-coding RNAs that negatively regulate gene expression. Importantly, microRNA activity has been linked to the control of cellular stress response. In the present study, we investigated whether the expression of hepatic microRNAs is affected by changes in ambient osmolarity. It is shown that hyperosmotic exposure of perfused rat liver induces a rapid upregulation of miR-15a, miR-15b and miR-16, which are members of the miR-15/107 microRNAs superfamily. It was also identified that hyperosmolarity significantly reduces the expression of anti-apoptotic genes including Bcl2, Ccnd1, Mcl1, Faim, Aatf, Bfar and Ikbkb, which are either validated or predicted targets of these microRNAs. Moreover, through the application of NOX and JNK inhibitors as well as benzylamine it is shown that the observed response is mediated by reactive oxygen species (ROS), suggesting that miR-15a, miR-15b and miR-16 are novel redoximiRs. It is concluded that the response of these three microRNAs to osmotic stress is ROS-mediated and that it might contribute to the development of a proapoptotic phenotype.

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The MicroRNA 15a/16–1 Cluster Down-regulates Protein Repair Isoaspartyl Methyltransferase in Hepatoma Cells

Cited by 17 publications

References 41 publications

Protein L-isoaspartyl methyltransferase regulates p53 activity

Protein L-isoaspartyl methyltransferase regulates p53 activity

Wortmannin Reduces Insulin Signaling and Death in Seizure-Prone Pcmt1−/− Mice

Hyperosmotic stress activates the expression of members of the miR-15/107 family and induces downregulation of anti-apoptotic genes in rat liver

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