Involvement of protein phosphatase 2A nuclear accumulation and subsequent inactivation of activator protein-1 in leptomycin B-inhibited cyclin D1 expression

Tsuchiya, Ayako; Tashiro, Etsu; Yoshida, Minoru; Imoto, Masaya

doi:10.1038/sj.onc.1209962

Cited by 17 publications

(18 citation statements)

References 58 publications

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“…PP2A has been implicated in cellular growth control primarily based on the discovery that okadaic acid, an inhibitor of PP2A activity, is a potent tumor promoter (9). Whereas the mechanism underlying this observation remained elusive, it was shown that PP2A suppression leads to activation of the mitogen-activated protein kinase pathway in the absence of growth factor-initiated signaling, whereas PP2A is inactivated in response to cell growth stimulation (9,49). Additionally, certain oncoproteins interact with PP2A, thus impairing its function (9), and specific PP2A complexes have been found to be up-regulated in transformed cells (49).…”

Section: Discussionmentioning

confidence: 99%

Protein Phosphatase 2A and Rapamycin Regulate the Nuclear Localization and Activity of the Transcription Factor GLI3

Krauß

Foerster²,

Schneider

et al. 2008

Cancer Research

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Gain-of-function alterations to the sonic hedgehog (SHH) signaling cascade have been found in a wide range of tumors. Three SHH effectors, GLI1, GLI2, and GLI3, regulate transcription of diverse genes involved in cell growth and cell proliferation. Here, we show that protein phosphatase 2A (PP2A), its regulatory subunit, A4, and rapamycin, an inhibitor of the mammalian target of rapamycin kinase complex 1 (mTORC1), regulate the nuclear localization and transcriptional activity of GLI3. An increase in PP2A activity or treatment with rapamycin leads to cytosolic retention of GLI3 and, consequently, reduced transcription of the GLI3 target gene and cell cycle regulator, cyclin D1. Conversely, inhibition of PP2A results in increased expression of cyclin D1. In summary, our findings reveal the existence of a hitherto unrecognized molecular cross-talk between the oncogenic SHH pathway and the tumor suppressor PP2A and suggest a novel mechanism underlying the anticancerogenic effects of rapamycin. [Cancer Res 2008;68(12):4658-65]

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Section: Discussionmentioning

confidence: 99%

Protein Phosphatase 2A and Rapamycin Regulate the Nuclear Localization and Activity of the Transcription Factor GLI3

Krauß

Foerster²,

Schneider

et al. 2008

Cancer Research

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“…SCADS inhibitor kits I to III were kindly provided by the Screening Committee of Anticancer Drugs in Japan (28,29). For further characterization after screening, rapamycin (WAKO), KT5823 (WAKO), Akt Inhibitor VIII (Merck), actinomycin D (WAKO), and trichostatin A (WAKO) were used.…”

Section: Methodsmentioning

confidence: 99%

“…To identify signaling factors that potentially contribute to the regulation of MT1-MMP/ Mint3-dependent HIF-1 activation, we screened a panel of 252 well-characterized signaling inhibitors (28,29) by using a luciferase reporter assay to monitor the FIH-1-dependent HIF-1␣ activity in HT1080 cells (Fig. 1A).…”

Section: Screening For Inhibitors Of Mt1-mmp/mint3-mediated Posttransmentioning

confidence: 99%

Hypoxia-Inducible Factor 1 Regulation through Cross Talk between mTOR and MT1-MMP

Sakamoto

Weng

Hara

et al. 2014

Molecular and Cellular Biology

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“…Tsuchiya et al (21) reported a potential NES in the C-subunit although individual sequences were not tested for export function. We investigated the possible role of B56␣ in regulating C-subunit localization, given that transiently expressed B56␣ is known to associate with the C-subunit (7).…”

Section: Identification Of Critical Residues In the B56␣ Nes And Evidmentioning

confidence: 99%

Nuclear Export and Centrosome Targeting of the Protein Phosphatase 2A Subunit B56α

Flegg

Sharma

Medina-Palazon

et al. 2010

Journal of Biological Chemistry

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Protein phosphatase (PP) 2A is a heterotrimeric enzyme regulated by specific subunits. The B56 (or B/PR61/PPP2R5) class of B-subunits direct PP2A or its substrates to different cellular locations, and the B56␣, -␤, and -⑀ isoforms are known to localize primarily in the cytoplasm. Here we studied the pathways that regulate B56␣ subcellular localization. We detected B56␣ in the cytoplasm and nucleus, and at the nuclear envelope and centrosomes, and show that cytoplasmic localization is dependent on CRM1-mediated nuclear export. The inactivation of CRM1 by leptomycin B or by siRNA knockdown caused nuclear accumulation of ectopic and endogenous B56␣. Conversely, CRM1 overexpression shifted B56␣ to the cytoplasm. We identified a functional nuclear export signal at the C terminus (NES; amino acids 451-469), and site-directed mutagenesis of the NES (L461A) caused nuclear retention of full-length B56␣. Active NESs were identified at similar positions in the cytoplasmic B56-␤ and ⑀ isoforms, but not in the nuclear-localized B56-␦ or ␥ isoforms. The transient expression of B56␣ induced nuclear export of the PP2A catalytic (C) subunit, and this was blocked by the L461A NES mutation. In addition, B56␣ co-located with the PP2A active (A) subunit at centrosomes, and its centrosome targeting involved sequences that bind to the A-subunit. Fluorescence Recovery after Photobleaching (FRAP) assays revealed dynamic and immobile pools of B56␣-GFP, which was rapidly exported from the nucleus and subject to retention at centrosomes. We propose that B56␣ can act as a PP2A C-subunit chaperone and regulates PP2A activity at diverse subcellular locations.Reversible protein phosphorylation is a key mechanism regulating a myriad of cellular processes. A delicate balance between the opposing effects of protein kinases and phosphatases determines the functional state of many proteins. Protein phosphatase 2A (PP2A) 3 refers to a major family of heterotrimeric serine-threonine phosphatase enzymes in the cell (1-3). The core enzyme is a dimer consisting of a 36-kDa catalytic C-subunit and a 65-kDa structural regulatory A-subunit, which acts as a scaffold to bring into proximity the C-subunit and protein substrates bound by the diverse regulatory B-subunits. There are four B-subunit gene families each with multiple genes that encode a range of splice variant peptides. The diverse nature of PP2A is inherent in its composition, which is potentially comprised of over 200 distinct protein complexes each containing different combinations of the A-, B-, and C-subunits, and hence allowing for variability and subtle regulation in phosphatase action (3).The B-subunits are postulated to regulate PP2A activity in different ways: (a) by targeting the holoenzyme to specific subcellular locations (e.g. B55␣ directs PP2A to microtubules (4)), (b) determining substrate specificity (e.g. PP2A complexes containing B55 or B72 B-subunits cause the activation or inhibition of SV40 DNA replication, respectively, because of differences in substrate recognition sites on...

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Involvement of protein phosphatase 2A nuclear accumulation and subsequent inactivation of activator protein-1 in leptomycin B-inhibited cyclin D1 expression

Cited by 17 publications

References 58 publications

Protein Phosphatase 2A and Rapamycin Regulate the Nuclear Localization and Activity of the Transcription Factor GLI3

Protein Phosphatase 2A and Rapamycin Regulate the Nuclear Localization and Activity of the Transcription Factor GLI3

Hypoxia-Inducible Factor 1 Regulation through Cross Talk between mTOR and MT1-MMP

Nuclear Export and Centrosome Targeting of the Protein Phosphatase 2A Subunit B56α

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