Transforming Growth Factor β and Ras/MEK/ERK Signaling Regulate the Expression Level of a Novel Tumor Suppressor Lefty

Miyata, Naoteru; Azuma, Toshifumi; Hozawa, Shigenari; Higuchi, Hajime; Yokoyama, Akiko; Kabashima, Ayano; Igarashi, Toru; Saeki, Kimiko; Hibi, Toshifumi

doi:10.1097/mpa.0b013e31823b66d3

Cited by 23 publications

(24 citation statements)

References 54 publications

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“…Given prior evidence of SMAD-independent MAPK activation downstream of TGF-␤ signaling (45,46), we hypothesize that the observed activation of TGF-␤ signaling might be a compensatory mechanism either partially or primarily aimed at SMAD-independent MAPK signaling activation upstream of RAS to counteract MAPK blockade produced by the inhibitors. These results provide further support for the argument that combination therapy with MAPK and TGF-␤ inhibitors may have potential benefits in the treatment of KRAS-driven cancers (50,51).…”

Section: Mib-prm Identifies Activation Of Tgf-␤ Signaling As a Compensupporting

confidence: 70%

An Optimized Chromatographic Strategy for Multiplexing In Parallel Reaction Monitoring Mass Spectrometry: Insights from Quantitation of Activated Kinases

Tlsty

Levin

Gordan

et al. 2017

Molecular & Cellular Proteomics

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Kinases are involved in the regulation of most cellular processes and are implicated in numerous human disease states. Five hundred and eighteen human kinases are known, and between 200 and 400 are typically expressed in a given cell type (1-3). Quantitative measurement of kinase activity is of critical importance in numerous biological applications, including studies of cellular signaling, cancer biomarker discovery, and drug development. An ideal strategy for functional kinase analysis must combine an active state kinase enrichment component and a methodology to quantify their levels of activation, because kinase regulation is a major determinant of cellular function and disease phenotypes.We and other groups have previously reported on the development and use of Multidrug Inhibitor Beads (MIB) 1 strategy for active kinase enrichment (4 -8). In this approach, kinase affinity enrichment scaffolds based on known kinase inhibitor structures targeted to conformationally active kinases are chemically coupled to a resin, which is used to capture broad classes of kinases from cell lysates (see recent review of this and related approaches by Daub (4)). When

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Section: Mib-prm Identifies Activation Of Tgf-␤ Signaling As a Compensupporting

confidence: 70%

An Optimized Chromatographic Strategy for Multiplexing In Parallel Reaction Monitoring Mass Spectrometry: Insights from Quantitation of Activated Kinases

Tlsty

Levin

Gordan

et al. 2017

Molecular & Cellular Proteomics

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“…Lefty exerted an inhibitory effect on the tumor-promoting function of Nodal, as recombinant Lefty suppressed Nodal-mediated proliferation [17]. Western blot analysis also revealed that hESC-derived Lefty significantly diminished Nodal protein expression in C8161 and MDA-MB-231 cells [6].…”

Section: Introductionmentioning

confidence: 93%

Lefty inhibits glioma growth by suppressing Nodal-activated Smad and ERK1/2 pathways

Sun¹,

Shi²,

Li³

et al. 2014

Journal of the Neurological Sciences

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“…We therefore investigated the effects of TGF‐β on Lefty expression in somatic cells. We recently reported that Lefty expression is induced by TGF‐β in several pancreatic cancer cell lines, all of which contained a ras mutation (12). We found that the canonical TGF‐β pathway is important for Lefty expression and that inhibition of ras‐MAPK signaling potentiates Lefty expression more than 10‐fold.…”

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confidence: 99%

Suppression ofLeftyexpression in induced pluripotent cancer cells

Saito¹,

Ochiai²,

Okada³

et al. 2013

FASEB j.

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Cancer and stem cells share the ability to silence tumor suppressors. We focused on Lefty, which encodes one of the most abundant tumor suppressors in embryonic stem (ES) cells and is not expressed in somatic cancer cells. We found that transforming growth factor β (TGF-β) induced demethylation of the Lefty B cytosine-phosphate-guanine (CpG) island and increased Lefty expression (10-200 times) in human pancreatic cancer cells and human liver cancer cells (PLC/PRF/5 and HLF). Expression of Cripto, another important factor in Nodal-Lefty signaling, was not increased after adding TGF-β. We generated reprogrammed cancer cells that revealed high expression of immature marker proteins, high proliferation, and the potential to express morphological patterns of ectoderm, mesoderm, and endoderm, suggesting that these cells may have cancer stem cell-like phenotypes. We investigated Lefty and found that reprogrammed human liver cancer cells (induced pluripotent cancer cells) displayed a much lower ability to express Lefty, although less Lefty B CpG methylation was also observed. We also found that a MEK inhibitor dramatically enhanced Lefty expression in human pancreatic cancers with mutated ras, whereas Lefty B CpG methylation was not decreased. These observations indicate that despite the demethylation of DNA strands in promoter regions of pluripotency-associated genes, including Lefty gene, Lefty expression was not induced well in reprogrammed cells. Of note was the fact that Lefty is abundantly expressed in human ES cells but not in induced pluripotent stem (iPS) cells. We thus think that reprogrammed cancer cells share the mechanism for expression of Lefty with iPS cells. This shared mechanism may contribute to the cancerous transformation of iPS cells.

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Transforming Growth Factor β and Ras/MEK/ERK Signaling Regulate the Expression Level of a Novel Tumor Suppressor Lefty

Cited by 23 publications

References 54 publications

An Optimized Chromatographic Strategy for Multiplexing In Parallel Reaction Monitoring Mass Spectrometry: Insights from Quantitation of Activated Kinases

An Optimized Chromatographic Strategy for Multiplexing In Parallel Reaction Monitoring Mass Spectrometry: Insights from Quantitation of Activated Kinases

Lefty inhibits glioma growth by suppressing Nodal-activated Smad and ERK1/2 pathways

Suppression ofLeftyexpression in induced pluripotent cancer cells

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