10-Formyltetrahydrofolate Dehydrogenase–Induced c-Jun-NH2-Kinase Pathways Diverge at the c-Jun-NH2-Kinase Substrate Level in Cells with Different p53 Status

Ghose, Sampa; Oleinik, Natalia; Krupenko, Natalia I.; Krupenko, Sergey A.

doi:10.1158/1541-7786.mcr-08-0309

Cited by 17 publications

(15 citation statements)

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“…High YAP activity enables the cell to circumvent contact inhibition, induces epithelial-mesenchymal transition, and eventually tumor development [40]. ALDH1L1, on the other hand, is silent in malignant tumors, and its re-expression in cancer cells elicits antiproliferative effects [35,41]. This may explain our finding that ALDH1L1 was highly expressed in astrocytes following YAP knockdown, and that BM-MSC-induced astrocyte proliferation was attenuated due to the subsequent blockage of YAP-TEAD interactions.…”

Section: Discussionmentioning

confidence: 89%

Bone marrow mesenchymal stem cells transplantation alleviates brain injury after intracerebral hemorrhage in mice through the Hippo signaling pathway

Xiao

Liang

et al. 2020

Aging

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Intracerebral hemorrhage (ICH) is a common acute nervous system disease with high mortality and severe disability. Mesenchymal stem cells (MSCs) have been reported to promote neurogenesis and to alleviate side effects in areas of brain injury areas. The Hippo pathway regulates diverse cellular processes, including cell survival, proliferation, differentiation, and organ size. Here, we found that transplantation of bone marrow MSCs (BM-MSCs) into the brains of mice could alleviate ICH-mediated injury and protect astrocytes from apoptosis by regulating mammalian sterile 20-like kinase (MST)1 and Yes-associated protein (YAP). Knocking down of MST1 by si-RNA triggered YAP nuclear translocation. We further demonstrated that astrocytes undergo astroglial-mesenchymal phenotype switching and become capable of proliferating after BM-MSC transplantation via the Hippo signaling pathway. Together, our identification of the Hippo pathway in mediating the beneficial effects of BM-MSCs may provide a novel therapeutic target in the treatment and management of ICH.

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Section: Discussionmentioning

confidence: 89%

Bone marrow mesenchymal stem cells transplantation alleviates brain injury after intracerebral hemorrhage in mice through the Hippo signaling pathway

Xiao

Liang

et al. 2020

Aging

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“…In addition to its strong down-regulation in cancers (with complete silencing in many cases), 5,11,32 FDH induces distinct apoptotic cascades with c-Jun N-terminal kinases and p53 as downstream mediators. [33][34][35] Canonical tumor suppressor genes, however, have been viewed as those deleted or mutated in cancer, 36,37 which is not the case for ALDH1L1. Numerous studies have also demonstrated epigenetic alterations of tumor suppressor genes in human cancers, which often result in repression of the transcription.…”

Section: Discussionmentioning

confidence: 99%

Epigenetic Silencing of ALDH1L1, a Metabolic Regulator of Cellular Proliferation, in Cancers

Oleinik

Krupenko

2011

Genes & Cancer

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FDH (10-formyltetrahydrofolate dehydrogenase, the product of the ALDH1L1 gene), a major folate-metabolizing enzyme in the cytosol, is involved in the regulation of cellular proliferation. We have previously demonstrated that FDH is strongly and ubiquitously down-regulated in malignant human tumors and cancer cell lines. Here, we report that promoter methylation is a major mechanism controlling FDH levels in human cancers. A computational analysis has identified an extensive CpG island in the ALDH1L1 promoter region. It contains 96 CpG pairs and covers the region between −525 and +918 bp of the ALDH1L1 gene including the promoter, the entire exon 1, and a part of intron 1 immediately downstream of the exon. Bisulfite sequencing analysis revealed extensive methylation of the island (76%-95% of CpGs) in cancer cell lines. In agreement with these findings, treatment of FDHdeficient A549 cells with the methyltransferase inhibitor 5-aza-2′-deoxycytidine restored FDH expression. Analysis of the samples from patients with lung adenocarcinomas demonstrated methylation of the ALDH1L1 CpG island in tumor samples and a total lack of methylation in respective normal tissues. The same phenomenon was observed in liver tissues: the CpG island was methylation free in DNA extracted from normal hepatocytes but was extensively methylated in a hepatocellular carcinoma. Levels of ALDH1L1 mRNA and protein correlated with the methylation status of the island, with tumor samples demonstrating down-regulation of expression or even complete silencing of the gene. Our studies have also revealed that exon 1 significantly increases transcriptional activity of ALDH1L1 promoter in a luciferase reporter assay. Interestingly, the exon is extensively methylated in samples with a strongly down-regulated or silenced ALDH1L1 gene. Keywords ALDH1L1, CpG island methylation, folate metabolism, lung adenocarcinomaOriginal Article

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“…We have previously shown that antiproliferative effects of FDH are associated with activation of JNKs and p53 as downstream effectors ( Ghose et al , 2009 ; Oleinik et al , 2007 ; Oleinik et al , 2005 ). These central players in controlling cellular proliferation are also implicated in regulation of migration ( Roger et al , 2006 ; Williams et al , 2006 ; Xia and Karin, 2004 ).…”

Section: Discussionmentioning

confidence: 99%

ALDH1L1 inhibits cell motility via dephosphorylation of cofilin by PP1 and PP2A

Oleinik

Krupenko

2010

Oncogene

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Here we report that ALDH1L1 (FDH, a folate enzyme with tumor suppressor-like properties) inhibits cell motility. The underlying mechanism involves F-actin stabilization, re-distribution of cytoplasmic actin towards strong preponderance of filamentous actin, and formation of actin stress fibers. A549 cells expressing FDH demonstrated a much slower recovery of GFP-actin fluorescence in a FRAP assay, as well as an increase in G-actin polymerization and a decrease in F-actin depolymerization rates in pyren-actin fluorescence assays indicating the inhibition of actin dynamics. These effects were associated with robust dephosphorylation of the actin depolymerizing factor cofilin by PP1 and PP2A serine/threonine protein phosphatases but not the cofilin-specific phosphatases slingshot and chronophin. In fact, the PP1/PP2A inhibitor calyculin prevented cofilin dephosphorylation and restored motility. Inhibition of FDH-induced apoptosis by the JNK inhibitor SP600125 or the pan-caspase inhibitor zVAD-fmk did not restore motility or levels of phospho-cofilin, indicating that the observed effects are independent from FDH function in apoptosis. Interestingly, cofilin siRNA or expression of phosphorylation-deficient S3A cofilin mutant resulted in a decrease of G-actin and the actin stress fiber formation, the effects seen upon FDH expression. In contrast, the expression of S3D mutant, mimicking constitutive phosphorylation, prevented these effects further supporting the cofilin-dependent mechanism. Dephosphorylation of cofilin and inhibition of motility in response to FDH can be also prevented by the increased folate in media. Furthermore, folate depletion itself, in the absence of FDH, resulted in cofilin dephosphorylation and inhibition of motility in several cell lines. Our experiments showed that these effects were folate-specific and not a general response to nutrient starvation. Overall, this study demonstrates the presence of distinct intracellular signaling pathways regulating motility in response to folate status and points toward mechanisms involving folates in promoting a malignant phenotype.

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10-Formyltetrahydrofolate Dehydrogenase–Induced c-Jun-NH2-Kinase Pathways Diverge at the c-Jun-NH2-Kinase Substrate Level in Cells with Different p53 Status

Abstract: 10-Formyltetrahydrofolate dehydrogenase (FDH)

Cited by 17 publications

References 50 publications

Bone marrow mesenchymal stem cells transplantation alleviates brain injury after intracerebral hemorrhage in mice through the Hippo signaling pathway

Bone marrow mesenchymal stem cells transplantation alleviates brain injury after intracerebral hemorrhage in mice through the Hippo signaling pathway

Epigenetic Silencing of ALDH1L1, a Metabolic Regulator of Cellular Proliferation, in Cancers

ALDH1L1 inhibits cell motility via dephosphorylation of cofilin by PP1 and PP2A

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