Polycomb Group Protein PHF1 Regulates p53-dependent Cell Growth Arrest and Apoptosis

Yang, Yang; Wang, Chenji; Zhang, Pingzhao; Gao, Kun; Wang, Dejie; Yu, Hongxiu; Zhang, Ting; Jiang, Shirui; Saiyin, Hexige; Zhang, Hong; Yasui, Akira; Liu, Jun O.; Huang, Haojie; Liu, Yu

doi:10.1074/jbc.m111.338996

Cited by 29 publications

(33 citation statements)

References 20 publications

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“…We also show that the Nterminal PHD domain of PCL1 has diverged functionally from that of PCL2 and PCL3 by using two unique serine residues to physically interact with the p53 C-terminal domain (CTD). As reported previously, the interaction of PCL1 with p53 leads to stabilization of p53 protein levels and increased expression of p53 target genes (Yang et al 2013); however, we further show that this increase in p53 levels is associated with induction of cellular quiescence. Conversely, depletion of PCL1 in quiescent cells phenocopies p53 loss, leading to a failure to maintain cellular quiescence.…”

supporting

confidence: 85%

“…This PHD domain shares a 38% sequence identity with the PHD domain of TRIM24, which has been cocrystalized with its H3(1-10)K4 substrate peptide (Tsai et al 2010). Interestingly, the CTD of p53, which is the minimal region of p53 required for interaction with PCL1 (Yang et al 2013), also bears sequence similarities to H3(1-10). Molecular dynamics simulations of a homology model of the PCL1 PHD1 based on the TRIM24 PHD-H3(1-10)K4 complex suggest that two serine residues (S95 and S106) could be essential for determining the specificity of PCL1 for p53 (Fig.…”

Section: The Ability Of the Pcl1 Phd Domain To Bind The P53 Ctd Is A mentioning

confidence: 98%

“…A recent study established that PCL1 interacts with and stabilizes p53 by blocking MDM2-mediated ubiquitination (Hong et al 2008;Yang et al 2013). To determine whether this interaction is specific to PCL1 and not PCL2 and PCL3, we performed endogenous coimmunoprecipitations (co-IPs) of p53 and PCL1-3 in HDFs ( Fig.…”

Section: Pcl1 Specifically Binds and Stabilizes P53 To Block Cellularmentioning

confidence: 99%

“…Previous work demonstrated that an N-terminal region encompassing the first PHD domain (PHD1) and a C-terminal region termed "BD2" mediate the ability of PCL1 to bind p53 and block MDM2-mediated ubiquitinylation of p53 (Yang et al 2013) …”

Section: Two Divergent Domains In Pcl1 Are Required and Sufficient Fomentioning

confidence: 99%

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A chromatin-independent role of Polycomb-like 1 to stabilize p53 and promote cellular quiescence

et al. 2015

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Polycomb-like proteins 1-3 (PCL1-3) are substoichiometric components of the Polycomb-repressive complex 2 (PRC2) that are essential for association of the complex with chromatin. However, it remains unclear why three proteins with such apparent functional redundancy exist in mammals. Here we characterize their divergent roles in both positively and negatively regulating cellular proliferation. We show that while PCL2 and PCL3 are E2F-regulated genes expressed in proliferating cells, PCL1 is a p53 target gene predominantly expressed in quiescent cells. Ectopic expression of any PCL protein recruits PRC2 to repress the INK4A gene; however, only PCL2 and PCL3 confer an INK4A-dependent proliferative advantage. Remarkably, PCL1 has evolved a PRC2-and chromatin-independent function to negatively regulate proliferation. We show that PCL1 binds to and stabilizes p53 to induce cellular quiescence. Moreover, depletion of PCL1 phenocopies the defects in maintaining cellular quiescence associated with p53 loss. This newly evolved function is achieved by the binding of the PCL1 N-terminal PHD domain to the C-terminal domain of p53 through two unique serine residues, which were acquired during recent vertebrate evolution. This study illustrates the functional bifurcation of PCL proteins, which act in both a chromatin-dependent and a chromatin-independent manner to regulate the INK4A and p53 pathways.

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supporting

confidence: 85%

Section: The Ability Of the Pcl1 Phd Domain To Bind The P53 Ctd Is A mentioning

confidence: 98%

Section: Pcl1 Specifically Binds and Stabilizes P53 To Block Cellularmentioning

confidence: 99%

Section: Two Divergent Domains In Pcl1 Are Required and Sufficient Fomentioning

confidence: 99%

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A chromatin-independent role of Polycomb-like 1 to stabilize p53 and promote cellular quiescence

et al. 2015

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“…In addition to its functions in PcGs, PHF1 also plays an important role in double-strand break (DSB) signaling and promoting non-homologous end-joining repair through interaction with Ku70/Ku80 [47] , thus playing a critical role in genome maintenance processes. Another feature worthy of attention is the ability of PHF1 to bind and protect p53 from MDM2-mediated ubiquitination and degradation [48] , implicating PHF1 in regulating cell growth arrest and apoptosis. MTF2/PCL2 function has been mainly analyzed in ES cells, where it is a component of biochemically distinct PRC2 com- plexes that it recruits to HOX genes and other target loci to regulate transcriptional networks during axial development [49,50] .…”

Section: Introductionmentioning

confidence: 99%

Structure of the PRC2 complex and application to drug discovery

et al. 2017

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The polycomb repressive complexes 2 (PRC2) complex catalyzes tri-methylation of histone H3 lysine 27 (H3K27), a repressive chromatin marker associated with gene silencing. Overexpression and mutations of PRC2 are found in a wide variety of cancers, making the catalytic activity of PRC2 an important target of cancer therapy. This review highlights recent structural breakthroughs of the human PRC2 complex bound to the H3K27 peptide and a small molecule inhibitor, which provide critically needed insight into PRC2-targeted drug discovery.

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Mutations and deletions of PRC2 in prostate cancer

Jain

Croce

2016

BioEssays

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The Polycomb group of proteins (PcGs) are transcriptional repressor complexes that regulate important biological processes and play critical roles in cancer. Mutating or deleting EZH2 can have both oncogenic and tumor suppressive functions by increasing or decreasing H3K27me3. In contrast, mutations of SUZ12 and EED are reported to have tumor suppressive functions. EZH2 is overexpressed in many cancers, including prostate cancer, which can lead to silencing of tumor suppressors, genes regulating epithelial to mesenchymal transition (EMT), and interferon signaling. In some cases, EZH2 overexpression also leads to its use of non-histone substrates. Lastly, PRC2 associated factors can influence the progression of cancer through progressive mutations or by specific binding to certain target genes. Here, we discuss which mutations and deletions of the PRC2 complex have been detected in different cancers, with a specific focus on the overexpression of EZH2 in prostate cancer.

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Polycomb Group Protein PHF1 Regulates p53-dependent Cell Growth Arrest and Apoptosis

Cited by 29 publications

References 20 publications

A chromatin-independent role of Polycomb-like 1 to stabilize p53 and promote cellular quiescence

A chromatin-independent role of Polycomb-like 1 to stabilize p53 and promote cellular quiescence

Structure of the PRC2 complex and application to drug discovery

Mutations and deletions of PRC2 in prostate cancer

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