Protein phosphatase PP1‐NIPP1 activates mesenchymal genes in HeLa cells

Dessel, Nele Van; Boens, Shannah; Lesage, Bart; Winkler, C; Görnemann, Janina; Eynde, Aleyde Van

doi:10.1016/j.febslet.2015.04.017

Cited by 14 publications

(7 citation statements)

References 27 publications

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“…S1C). A very mild overexpression of NIPP1 in stable HeLa cell lines (<10%), due to promoter leakage from the non-induced transgenes, causes the expression of mesenchymal genes (Van Dessel et al, 2015). However, this low level of overexpression had no effect on the progression through mitosis (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Hela Tet-off cell lines expressing Flag-tagged NIPP1 variants in the absence of doxycycline (Dox) and Flip-In T-REx cell lines expressing EGFP or EGFP-tagged NIPP1 variants in the presence of Dox were obtained as described previously (Tanuma et al, 2008;Van Dessel et al, 2015). Transfections were carried out using a commercial kit (Jet-Prime, Polyplus), according to the manufacturer's instructions.…”

Section: Cell Culture and Imagingmentioning

confidence: 99%

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The selective inhibition of protein phosphatase-1 results in mitotic catastrophe and impaired tumor growth

Winkler

Munter

Dessel

et al. 2015

Journal of Cell Science

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The serine/threonine protein phosphatase-1 (PP1) complex is a key regulator of the cell cycle. However, the redundancy of PP1 isoforms and the lack of specific inhibitors have hampered studies on the global role of PP1 in cell cycle progression in vertebrates. Here, we show that the overexpression of nuclear inhibitor of PP1 (NIPP1; also known as PPP1R8) in HeLa cells culminated in a prometaphase arrest, associated with severe spindle-formation and chromosome-congression defects. In addition, the spindle assembly checkpoint was activated and checkpoint silencing was hampered. Eventually, most cells either died by apoptosis or formed binucleated cells. The NIPP1-induced mitotic arrest could be explained by the inhibition of PP1 that was titrated away from other mitotic PP1 interactors. Consistent with this notion, the mitoticarrest phenotype could be rescued by the overexpression of PP1 or the inhibition of the Aurora B kinase, which acts antagonistically to PP1. Finally, we demonstrate that the overexpression of NIPP1 also hampered colony formation and tumor growth in xenograft assays in a PP1-dependent manner. Our data show that the selective inhibition of PP1 can be used to induce cancer cell death through mitotic catastrophe.

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Section: Discussionmentioning

confidence: 99%

Section: Cell Culture and Imagingmentioning

confidence: 99%

The selective inhibition of protein phosphatase-1 results in mitotic catastrophe and impaired tumor growth

Winkler

Munter

Dessel

et al. 2015

Journal of Cell Science

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“…There are no data available regarding alterations in PP1 activity and/or substrate phosphorylation for the inducible and conditional NIPP1 KOs. However, various biochemical and cellular assays have revealed that known cellular NIPP1 functions (pre-mRNA splicing and transcription) are largely dependent on both association with PP1 and recruitment of substrates [38,110,114]. Mice that inducibly express the central part of NIPP1 (NIPP1 ) in the forebrain showed a decreased nuclear PP1 activity and increased histone H3 phosphorylation at serine 10 ( Table 3).…”

Section: Cellular-context Dependent Functions Of Nipp1mentioning

confidence: 99%

Functions and therapeutic potential of protein phosphatase 1: Insights from mouse genetics

Ferreira

Beullens

Eynde

2019

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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Protein phosphatase 1 (PP1) catalyzes more than half of all phosphoserine/threonine dephosphorylation reactions in mammalian cells. In vivo PP1 does not exist as a free catalytic subunit but is always associated with at least one regulatory PP1-interacting protein (PIP) to generate a large set of distinct holoenzymes. Each PP1 complex controls the dephosphorylation of only a small subset of PP1 substrates. We screened the literature for genetically engineered mouse models and identified models for all PP1 isoforms and 104 PIPs. PP1 itself and at least 49 PIPs were connected to human disease-associated phenotypes. Additionally, phenotypes related to 17 PIPs were clearly linked to altered PP1 function, while such information was lacking for 32 other PIPs. We propose structural reverse genetics, which combines structural characterization of proteins with mouse genetics, to identify new PP1-related therapeutic targets. The available mouse models confirm the pleiotropic action of PP1 in health and diseases.

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“…NIPP1 can silence transcription as it constitutes part of a protein silencing complex that includes the transcriptional repressor EED and histone deacetylase HDAC2 [39, 40]. NIPP1 can also activate transcription as it induces expression of mesenchymal genes in HeLa cells [41]. We recently reported that NIPP1 represses expression of neuregulin-1, a heparin-binding neurotrophic factor [42].…”

Section: Regulation Of Hiv-1 Transcription By Protein Phosphatase-1mentioning

confidence: 99%

Protein Phosphatase-1 –targeted Small Molecules, Iron Chelators and Curcumin Analogs as HIV-1 Antivirals

Lin¹,

Ammosova²,

Kumari³

et al. 2017

CPD

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Background Despite efficient suppression of HIV-1 replication, current antiviral drugs are not able to eradicate HIV-1 infection. Permanent HIV-1 suppression or complete eradication requires novel biological approaches and therapeutic strategies. Our previous studies showed that HIV-1 transcription is regulated by host cell protein phosphatase-1. We also showed that HIV-1 transcription is sensitive to the reduction of intracellular iron that affects cell cycle-dependent kinase 2. We developed protein phosphatase 1-targeting small molecules that inhibited HIV-1 transcription. We also found an additional class of protein phosphatase-1-targeting molecules that activated HIV-1 transcription and reported HIV-1 inhibitory iron chelators and novel curcumin analogs that inhibit HIV-1. Here, we review HIV-1 transcription and replication with focus on its regulation by protein phosphatase 1 and cell cycle dependent kinase 2 and describe novel small molecules that can serve as future leads for anti-HIV drug development. Results Our review describes in a non-exhaustive manner studies in which HIV-1 transcription and replication are targeted with small molecules. Previously, published studies show that HIV-1 can be inhibited with protein phosphatase-1-targeting and iron chelating compounds and curcumin analogs. These results are significant in light of the current efforts to eradicate HIV-1 through permanent inhibition. Also, HIV-1 activating compounds can be useful for “kick and kill” therapy in which the virus is reactivated prior to its inhibition by the combination antiretroviral therapy. Conclusion The studies described in our review point to protein phosphatase-1 as a new drug target, intracellular iron as subject for iron chelation and novel curcumin analogs that can be developed for novel HIV-1 transcription-targeting therapeutics.

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Protein phosphatase PP1‐NIPP1 activates mesenchymal genes in HeLa cells

Cited by 14 publications

References 27 publications

The selective inhibition of protein phosphatase-1 results in mitotic catastrophe and impaired tumor growth

The selective inhibition of protein phosphatase-1 results in mitotic catastrophe and impaired tumor growth

Functions and therapeutic potential of protein phosphatase 1: Insights from mouse genetics

Protein Phosphatase-1 –targeted Small Molecules, Iron Chelators and Curcumin Analogs as HIV-1 Antivirals

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