Alterations of Deadenylase Expression in Acute Leukemias: Evidence for Poly(A)-Specific Ribonuclease as a Potential Biomarker

Maragozidis, Panagiotis; Karangeli, Maria; Labrou, Maria; Dimoulou, Georgia; Papaspyrou, Konstantia; Salataj, Eralda; Pournaras, Spyridon; Matsouka, Panagiota; Gourgoulianis, Konstantinos; Balatsos, Nikolaos A. A.

doi:10.1159/000337418

Cited by 42 publications

(50 citation statements)

References 84 publications

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“…However, the knowledge remains very limited for the regulators of mRNA decay and the pairwise relationships for elements-factors-deadenylases [2]. PARN has been proposed to be a potential target of cancer treatment [7] and is highly expressed in acute leukemias [34] and gastric cancers (this research). Further research is needed to fully decipher the physiological/pathological functions and the key mRNA targets of PARN as well as the other deadenylases.…”

Section: Discussionmentioning

confidence: 99%

“…Knockdown of PARN increases the migration rate of mouse myoblasts [33]. Moreover, PARN has been found to have a high expression level in acute leukemias [34]. These observations suggest that PARN plays a role in cellular processes involving the action of p21.…”

Section: Introductionmentioning

confidence: 88%

“…Previous studies have shown that PARN has a high expression level in acute leukemia [34] and has been proposed to be a potential cancer therapeutic target [7]. To examine the expression status of PARN in human gastric cancer, semi-quantitative and real-time RT-PCR was used to examine the mRNA level of PARN in two human gastric cancer cell lines and six pairs of gastric tumor tissues from patients described elsewhere [35].…”

Section: Expression Level Of Parn In Human Gastric Cancer Cells and Tmentioning

confidence: 99%

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Depletion of poly(A)-specific ribonuclease (PARN) inhibits proliferation of human gastric cancer cells by blocking cell cycle progression

Zhang

Yan

2015

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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Regulation of mRNA decay plays a crucial role in the post-transcriptional control of cell growth, survival, differentiation, death and senescence. Deadenylation is a rate-limiting step in the silence and degradation of the bulk of highly regulated mRNAs. However, the physiological functions of various deadenylases have not been fully deciphered. In this research, we found that poly(A)-specific ribonuclease (PARN) was upregulated in gastric tumor tissues and gastric cancer cell lines MKN28 and AGS. The cellular function of PARN was investigated by stably knocking down the endogenous PARN in the MKN28 and AGS cells. Our results showed that PARN-depletion significantly inhibited the proliferation of the two types of gastric cancer cells and promoted cell death, but did not significantly affect cell motility and invasion. The depletion of PARN arrested the gastric cancer cells at the G0/G1 phase by upregulating the expression levels of p53 and p21 but not p27. The mRNA stability of p53 was unaffected by PARN-knockdown in both types of cells. A significant stabilizing effect of PARN-depletion on p21 mRNA was observed in the AGS cells but not in the MKN28 cells. We further showed that the p21 3'-UTR triggered the action of PARN in the AGS cells. The dissimilar observations between the MKN28 and AGS cells as well as various stress conditions suggested that the action of PARN strongly relied on protein expression profiles of the cells, which led to heterogeneity in the stability of PARN-targeted mRNAs.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 88%

Section: Expression Level Of Parn In Human Gastric Cancer Cells and Tmentioning

confidence: 99%

See 1 more Smart Citation

Depletion of poly(A)-specific ribonuclease (PARN) inhibits proliferation of human gastric cancer cells by blocking cell cycle progression

Zhang

Yan

2015

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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“…[94][95][96][97] PARN is phosphorylated and its levels are increased in acute lymphocytic leukemia (ALL), and acute myeloid leukemia (AML). 98 Similarly, PARN levels are altered in lung cancers, 95 suggesting a clinical significance of PARN in cancer apart from development. In G0, PARN cap binding and deadenylase activity increases, which causes deadenylation of mRNAs.…”

Section: Parn Is Essential For Fxr1a-micrornp Mediated Translation Asmentioning

confidence: 99%

“…59,121,[129][130][131][132][133] Consistently, components of the FXR1a-microRNP are implicated in cancer progression: FXR1 is known to promote tumor invasion and progression, 30 while its interacting partners, PARN and p97, are increased in activity or levels in many cancers. 98,134 Targeting components of the FXR1a-microRNP mechanism or associated microRNAs may help block translation of critical genes required for maintaining dormant cancer cells, and might be a promising approach against cancer recurrence.…”

Section: Fxr1a-micrornp Mediates Translation Of Important Genesmentioning

confidence: 99%

FXR1a-associated microRNP: A driver of specialized non-canonical translation in quiescent conditions

Bukhari

Vasudevan

2017

RNA Biology

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Eukaryotic protein synthesis is a multifaceted process that requires coordination of a set of translation factors in a particular cellular state. During normal growth and proliferation, cells generally make their proteome via conventional translation that utilizes canonical translation factors. When faced with environmental stress such as growth factor deprivation, or in response to biological cues such as developmental signals, cells can reduce canonical translation. In this situation, cells adapt alternative modes of translation to make specific proteins necessary for required biological functions under these distinct conditions. To date, a number of alternative translation mechanisms have been reported, which include non-canonical, cap dependent translation and cap independent translation such as IRES mediated translation. Here, we discuss one of the alternative modes of translation mediated by a specialized microRNA complex, FXR1a-microRNP that promotes non-canonical, cap dependent translation in quiescent conditions, where canonical translation is reduced due to low mTOR activity.

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Susceptibility loci of CNOT6 in the general mRNA degradation pathway and lung cancer risk—A re‐analysis of eight GWASs

Zhou

Wang

Liu

et al. 2016

Molecular Carcinogenesis

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Purpose mRNA degradation is an important regulatory step for controlling gene expression and cell functions. Genetic abnormalities of the genes involved in mRNA degradation were found to be associated with cancer risks. Therefore, we systematically investigated the roles of genetic variants of genes in the general mRNA degradation pathway in lung cancer risk. Experimental design Meta-analyses were conducted in six lung cancer genome-wide association studies (GWASs) from the Transdisciplinary Research in Cancer of the Lung and additional two GWASs from Harvard University and deCODE in the International Lung Cancer Consortium. Expression quantitative trait loci analysis (eQTL) was used for in silico functional validation of the identified significant susceptibility loci. Results This pathway-based analysis included 4,603 single nucleotide polymorphisms (SNP) in 68 genes in 14,463 lung cancer cases and 44,188 controls, of which 20 SNPs were found to be associated with lung cancer risk with a false discovery rate threshold of <0.05. Among the 11 newly identified SNPs in CNOT6, which were in high linkage disequilibrium, the rs2453176 with a RegulomDB score “1f” was chosen as the tag SNP for further analysis. We found that the rs2453176 T allele was significantly associated with lung cancer risk (odds ratio=1.11, 95% confidence interval=1.04–1.18, P=0.001) in the eight GWASs. In the eQTL analysis, we found that levels of CNOT6 mRNA expression were significantly correlated with the rs2453176 T allele, which provided additional biological basis for the observed positive association. Conclusion The CNOT6 rs2453176 SNP may be a new functional susceptible locus for lung cancer risk.

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Alterations of Deadenylase Expression in Acute Leukemias: Evidence for Poly(A)-Specific Ribonuclease as a Potential Biomarker

Cited by 42 publications

References 84 publications

Depletion of poly(A)-specific ribonuclease (PARN) inhibits proliferation of human gastric cancer cells by blocking cell cycle progression

Depletion of poly(A)-specific ribonuclease (PARN) inhibits proliferation of human gastric cancer cells by blocking cell cycle progression

FXR1a-associated microRNP: A driver of specialized non-canonical translation in quiescent conditions

Susceptibility loci of CNOT6 in the general mRNA degradation pathway and lung cancer risk—A re‐analysis of eight GWASs

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