Modulation of microRNA processing by mismatch repair protein MutLα

Mao, Guogen; Lee, Grace Sanghee; Ortega, Janice; Gu, Liya; Li, Guo Min

doi:10.1038/cr.2012.18

Cited by 40 publications

(37 citation statements)

References 49 publications

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“…A recent study implicates MutLα as a general stimulating factor for miRNA biogenesis, giving the complex an additional function in tumorigenesis (34). In our cohort of specimens we observed that a proportion of tumors exhibited mRNA overexpression of hMSH2, hMLH1 and hPMS2.…”

Section: Discussionmentioning

confidence: 50%

“…However, the hMLH1 gene was found to have elevated mRNA ratios (R 1 phenotype) both in UCCs and their ANTs, indicating either high requirements for DNA repair of the progressively increasing errors in cancerous or precancerous urothelium or the involvement of hMLH1 in another tumorigenesis pathway (33). The counterpart of hMLH1, hPMS2, was also overexpressed in a percentage of pT 1-2 and high grade UCCs, to cooperate with MLH1 as complex (MutLα) due to the demanding repair or another function (10,14,34). Nevertheless, a percentage of UCCs presented reduced levels of hMLH1 and hPMS2 mRNA expression relative to their ANTs which indicates low DNA repair activity in a large proportion of UCCs and therefore accumulation of replication errors in the abnormal proliferating malignant cells.…”

Section: Discussionmentioning

confidence: 99%

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Mismatch repair hMSH2, hMLH1, hMSH6 and hPMS2 mRNA expression profiles in precancerous and cancerous urothelium

et al. 2012

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Abstract. Changes in the expression of the mismatch repair (MMR) genes hMSH2, hMLH1, hMSH6 and hPMS2 reflect dysfunction of the DNA repair system that may allow the malignant transformation of tissue cells. The aim of the present study was to address the mRNA expression profiles of the mismatch DNA repair system in cancerous and precancerous urothelium. This is the first study to quantify MMR mRNA expression by applying quantitative real-time PCR (qPCR) and translate the results to mRNA phenotypic profiles (r, reduced; R, regular or elevated) in bladder tumors [24 urothelial cell carcinomas (UCCs) and 1 papillary urothelial neoplasm of low malignant potential (PUNLMP)] paired with their adjacent normal tissues (ANTs). Genetic instability analysis was applied at polymorphic sites distal or close to the hMSH2 and hMLH1 locus. Presenting our data, reduced hMSH2, hMSH6 and hPMS2 mRNA expression profiles were observed in cancerous and precancerous urothelia. Significantly, the ANTs of UCCs revealed the highest percentages of reduced hMSH2 (r 2 ), hMSH6 (r 6 ) and hPMS2 (p 2 ) mRNA phenotypes relative to their tumors (P<0.03). In particular, combined r 2 r 6 (P<0.02) presented a greater difference between ANTs of low-grade UCCs vs. their tumors compared with ANTs of high-grade UCCs (P= 0.000). Reduced hMLH1 (r 1 ) phenotype was not expressed in precancerous or cancerous urothelia. The hMSH6 mRNA was the most changed in UCCs (47.8%), while hMSH2, hMLH1 and hPMS2 showed overexpression (47.8, 35 and 30%, respectively) that was associated with gender and histological tumor grading or staging. Genetic instability was rare in polymorphic regions distal to hMLH1. Our data reveal a previously unrecognized hMSH2 and hMSH6 mRNA combined phenotype (r 2 r 6 ) correlated with a precancerous urothelium and show that hMLH1 is transcriptionally activated in precancerous or cancerous urothelium. In the present study, it is demonstrated that reduction of hMSH6 mRNA is a frequent event in bladder tumorigenesis and reflects a common mechanism of suppression with hMSH2, while alterations of hMSH2 or hMLH1 mRNA expression in UCCs does not correlate with the allelic imbalance of polymorphic regions harboring the genes. IntroductionThe most common histological type of bladder cancer is urothelial cell carcinoma (UCC) or transitional cell carcinoma (TCC). Papillary urothelial neoplasm of low malignant potential (PUNLMP) may also arise from urothelium of bladder (1,2). The urothelium of a patient with a bladder cancer is at risk as the cancer often recurrs in the urinary bladder following treatment (1,3). Numerous genetic and epigenetic factors have been implicated in the carcinogenesis of the urinary bladder that involved in its mutator phenotype (4-7). The DNA repair mechanism is essential to prevent DNA mutations that may be lethal for cells (8). Mismatch repair (MMR) genes encode a number of DNA repair enzymes that cooperate to recognize and repair DNA mismatches (8,9). These enzymes act as complexes. A crucial complex that recognizes base...

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Section: Discussionmentioning

confidence: 50%

Section: Discussionmentioning

confidence: 99%

Mismatch repair hMSH2, hMLH1, hMSH6 and hPMS2 mRNA expression profiles in precancerous and cancerous urothelium

et al. 2012

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“…Loss of CSF-1R Tyr-721 was associated with loss of CSF-1 induction of miR-21 ( Figure 4; supplemental Figure 4), which could be due to inefficient processing of miR-21 from its precursor forms, [78][79][80] decreased stability of mature miR-21, 81 or other processes. 82 To investigate the regulation of M1/M2 functions by miR-21, the predicted mRNA targets were validated and shown to predominantly encode molecules promoting an M1 phenotype (Figure 4; supplemental Tables 6-8).…”

Section: Discussionmentioning

confidence: 99%

Colony stimulating factor-1 receptor signaling networks inhibit mouse macrophage inflammatory responses by induction of microRNA-21

Caescu

Guo

Tesfa³

et al. 2015

Blood

123

118

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Key Points• Analysis of CSF-1R pTyrregulated messenger RNAs identifies novel signaling nodes and networks that can be targeted to modulate macrophage functions.• miR-21 is a novel CSF-1R pTyr-721-induced molecule that suppresses the macrophage M1 phenotype and enhances the M2 phenotype.Macrophage polarization between the M2 (repair, protumorigenic) and M1 (inflammatory) phenotypes is seen as a continuum of states. The detailed transcriptional events and signals downstream of colony-stimulating factor 1 receptor (CSF-1R) that contributes to amplification of the M2 phenotype and suppression of the M1 phenotype are largely unknown. Macrophage CSF-1R pTyr-721 signaling promotes cell motility and enhancement of tumor cell invasion in vitro. Combining analysis of cellular systems for CSF-1R gain of function and loss of function with bioinformatic analysis of the macrophage CSF-1R pTyr-721-regulated transcriptome, we uncovered microRNA-21 (miR-21) as a downstream molecular switch controlling macrophage activation and identified extracellular signal-regulated kinase 1/2 and nuclear factor-kB as CSF-1R pTyr-721-regulated signaling nodes. We show that CSF-1R pTyr-721 signaling suppresses the inflammatory phenotype, predominantly by induction of miR-21. Profiling of the miR-21-regulated messenger RNAs revealed that 80% of the CSF-1-regulated canonical miR-21 targets are proinflammatory molecules. Additionally, miR-21 positively regulates M2 marker expression. Moreover, miR-21 feeds back to positively regulate its own expression and to limit CSF-1R-mediated activation of extracellular signal-regulated kinase 1/2 and nuclear factor-kB. Consistent with an anti-inflammatory role of miRNA-21, intraperitoneal injection of mice with a miRNA-21 inhibitor increases the recruitment of inflammatory monocytes and enhances the peritoneal monocyte/macrophage response to lipopolysaccharide. These results identify the CSF-1R-regulated miR-21 network that modulates macrophage polarization. (Blood. 2015;125(8):e1-e13) IntroductionMacrophages protect the host against infection and injury and facilitate tissue remodeling.1 However, they frequently accumulate in pathological settings, including cancers, 2 atherosclerosis, 3 metabolic disease, 4 and sepsis, 5 where they respond to microenvironmental cues that can be detrimental to the host. Two distinct extreme states of polarized activation have been described in macrophages:6,7 the classically activated (M1) and the alternatively activated (M2) macrophage phenotypes, each characterized by well-described markers. 5,6,[8][9][10][11] M1 macrophages produce proinflammatory cytokines, elevate the expression of inducible nitric oxide synthase 2 (iNOS) and major histocompatibility complex class II (MHC II), 12 and can play antitumorigenic roles. 5,9 In contrast, the M2 macrophages have increased expression of scavenger receptors, increased activation of the arginase pathway, low expression of interleukin-12 (IL-12), high expression of IL-10 and IL-1RA, and increased anti-inflammatory responses a...

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“…The heterodimer MLH1-PMS2 (MutLα) has been shown to positively regulate the processing of miR-422a and other miRNAs by specifically stimulating the Drosha/DGCR8-catalyzed processing of pri-miRNAs to pre-miRNAs [87].…”

Section: Ber Enzymes and Mirna Regulation: A New Paradigm In Gene Expmentioning

confidence: 99%

Unveiling the non-repair face of the Base Excision Repair pathway in RNA processing: A missing link between DNA repair and gene expression?

2017

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Modulation of microRNA processing by mismatch repair protein MutLα

Cited by 40 publications

References 49 publications

Mismatch repair hMSH2, hMLH1, hMSH6 and hPMS2 mRNA expression profiles in precancerous and cancerous urothelium

Mismatch repair hMSH2, hMLH1, hMSH6 and hPMS2 mRNA expression profiles in precancerous and cancerous urothelium

Colony stimulating factor-1 receptor signaling networks inhibit mouse macrophage inflammatory responses by induction of microRNA-21

Unveiling the non-repair face of the Base Excision Repair pathway in RNA processing: A missing link between DNA repair and gene expression?

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