The GAS41-PP2Cβ Complex Dephosphorylates p53 at Serine 366 and Regulates Its Stability

Park, Jeong-Hyeon; Smith, Rebecca; Shieh, Sheau‐Yann; Roeder, Robert G.

doi:10.1074/jbc.c110.210211

Cited by 27 publications

(18 citation statements)

References 32 publications

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“…Part of its tumor-promoting activity is thought to be mediated through negative regulation of the p53 pathway. For example, GAS41 physically interacts with p53 and regulates p53 protein stability independently of the SRCAP or Tip60/ p400 complex (Park et al 2011). In addition, GAS41 is present at the promoters of p53-regulated genes, such as p21, and suppresses gene expression (Park and Roeder 2006;Pikor et al 2013).…”

Section: Discussionmentioning

confidence: 99%

Recognition of histone acetylation by the GAS41 YEATS domain promotes H2A.Z deposition in non-small cell lung cancer

et al. 2018

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Histone acetylation is associated with active transcription in eukaryotic cells. It helps to open up the chromatin by neutralizing the positive charge of histone lysine residues and providing binding platforms for "reader" proteins. The bromodomain (BRD) has long been thought to be the sole protein module that recognizes acetylated histones. Recently, we identified the YEATS domain of AF9 (ALL1 fused gene from chromosome 9) as a novel acetyl-lysine-binding module and showed that the ENL (eleven-nineteen leukemia) YEATS domain is an essential acetyl-histone reader in acute myeloid leukemias. The human genome encodes four YEATS domain proteins, including GAS41, a component of chromatin remodelers responsible for H2A.Z deposition onto chromatin; however, the importance of the GAS41 YEATS domain in human cancer remains largely unknown. Here we report that is frequently amplified in human non-small cell lung cancer (NSCLC) and is required for cancer cell proliferation, survival, and transformation. Biochemical and crystal structural studies demonstrate that GAS41 binds to histone H3 acetylated on H3K27 and H3K14, a specificity that is distinct from that of AF9 or ENL. ChIP-seq (chromatin immunoprecipitation [ChIP] followed by high-throughput sequencing) analyses in lung cancer cells reveal that GAS41 colocalizes with H3K27ac and H3K14ac on the promoters of actively transcribed genes. Depletion of GAS41 or disruption of the interaction between its YEATS domain and acetylated histones impairs the association of histone variant H2A.Z with chromatin and consequently suppresses cancer cell growth and survival both in vitro and in vivo. Overall, our study identifies GAS41 as a histone acetylation reader that promotes histone H2A.Z deposition in NSCLC.

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Section: Discussionmentioning

confidence: 99%

Recognition of histone acetylation by the GAS41 YEATS domain promotes H2A.Z deposition in non-small cell lung cancer

et al. 2018

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“…Also knockdown of PPM1B in wild-type ES cells did not affect proliferation suggesting that PPM1B expression is specifically required during the early stages of embryogenesis and does not affect cell-cycle progression [34]. So far, only a limited number of substrates for PPM1B have been identified, including the kinases IKKβ [IκB (inhibitor of nuclear factor κB) kinase] [35] and TAK1 (transforming growth factor-β-activated kinase 1) [36], the proapoptotic protein Bad [37], the cyclin-dependent kinases CDK2 and CDK6 [38], the transcription factor p53 [39] and the CDK9 subunit of P-TEFb (positive transcription elongation factor b) [40]. Interestingly, Iankova et al [9] showed that CDK9mediated phosphorylation of PPARγ on Ser 112 results in enhanced transcriptional activity.…”

Section: Discussionmentioning

confidence: 99%

The serine/threonine phosphatase PPM1B (PP2Cβ) selectively modulates PPARγ activity

Taşdelen

Beekum

Gorbenko

et al. 2013

Biochemical Journal

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Reversible phosphorylation is a widespread molecular mechanism to regulate the function of cellular proteins, including transcription factors. Phosphorylation of the nuclear receptor PPARγ (peroxisome-proliferator-activated receptor γ) at two conserved serine residue (Ser(112) and Ser(273)) results in an altered transcriptional activity of this transcription factor. So far, only a very limited number of cellular enzymatic activities has been described which can dephosphorylate nuclear receptors. In the present study we used immunoprecipitation assays coupled to tandem MS analysis to identify novel PPARγ-regulating proteins. We identified the serine/threonine phosphatase PPM1B [PP (protein phosphatase), Mg(2+)/Mn(2+) dependent, 1B; also known as PP2Cβ] as a novel PPARγ-interacting protein. Endogenous PPM1B protein is localized in the nucleus of mature 3T3-L1 adipocytes where it can bind to PPARγ. Furthermore we show that PPM1B can directly dephosphorylate PPARγ, both in intact cells and in vitro. In addition PPM1B increases PPARγ-mediated transcription via dephosphorylation of Ser(112). Finally, we show that knockdown of PPM1B in 3T3-L1 adipocytes blunts the expression of some PPARγ target genes while leaving others unaltered. These findings qualify the phosphatase PPM1B as a novel selective modulator of PPARγ activity.

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“…Furthermore, GAS41 is required for dephosphorylation of serine 366 on TP53 that forms a complex with PP2CB. The cell survival upon genotoxic DNA damage was increased after ectopic expression of GAS41 and PP2CB by reducing the TP53 upregulation (Park et al, 2011). NuMA appears to be a key to further understanding the role of GAS41 in mitosis.…”

Section: Discussionmentioning

confidence: 99%

GAS41 amplification results in overexpression of a new spindle pole protein

Schmitt

Fischer

Heisel

et al. 2012

Genes Chromosomes & Cancer

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Amplification is a hallmark of many human tumors but the role of most amplified genes in human tumor development is not yet understood. Previously, we identified a frequently amplified gene in glioma termed glioma-amplified sequence 41 (GAS41). Using the TCGA data portal and performing experiments on HeLa and TX3868, we analyzed the role of GAS41 amplification on GAS41 overexpression and the effect on the cell cycle. Here we show that GAS41 amplification is associated with overexpression in the majority of cases. Both induced and endogenous overexpression of GAS41 leads to an increase in multipolar spindles. We showed that GAS41 is specifically associated with pericentrosome material. As result of an increased GAS41 expression we found bipolar spindles with misaligned chromosomes. This number was even increased by a combined overexpression of GAS41 and a reduced expression of NuMA. We propose that GAS41 amplification may have an effect on the highly altered karyotype of glioblastoma via its role during spindle pole formation.

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The GAS41-PP2Cβ Complex Dephosphorylates p53 at Serine 366 and Regulates Its Stability

Cited by 27 publications

References 32 publications

Recognition of histone acetylation by the GAS41 YEATS domain promotes H2A.Z deposition in non-small cell lung cancer

Recognition of histone acetylation by the GAS41 YEATS domain promotes H2A.Z deposition in non-small cell lung cancer

The serine/threonine phosphatase PPM1B (PP2Cβ) selectively modulates PPARγ activity

GAS41 amplification results in overexpression of a new spindle pole protein

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