Phosphorylation of the Transcription Factor YY1 by CK2<i>α</i> Prevents Cleavage by Caspase 7 during Apoptosis

Riman, Sarah; Rizkallah, Raed; Kassardjian, Ari; Alexander, Karen E.; Lüscher, Bernhard; Hurt, Myra M.

doi:10.1128/mcb.06466-11

Cited by 32 publications

(32 citation statements)

References 70 publications

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“…CK2α is another kinase identified as constitutively phosphorylating YY1 at serine 118. This modification protects YY1 cleavage by caspase 7 during apoptosis [23]. Our lab also reported that phosphorylation of YY1 in the DNA binding domain (threonine 348 and threonine 378) during mitosis abolishes its DNA binding activity [7].…”

Section: Introductionmentioning

confidence: 68%

“…Multiple residues on YY1 are targets of post-translational modification, including, S-nitrosation [16], acetylation [17], [18], O-linked glycosylation [19], sumoylation [20], and poly(ADP-ribosyl)ation [21], [22], all of which regulate the function and activity of YY1. More recently, we identified and mapped multiple phosphorylation sites in YY1, including, threonine 39, serine 118, serine 247, threonine 348 and threonine 378 [7], [23]–[25]. The first kinase proven to phosphorylate YY1 in vivo was Plk1, which phosphorylates threonine 39 during G2/M stage of the cell cycle [25].…”

Section: Introductionmentioning

confidence: 99%

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The Transcription Factor YY1 Is a Novel Substrate for Aurora B Kinase at G2/M Transition of the Cell Cycle

et al. 2012

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Yin Yang 1 (YY1) is a ubiquitously expressed and highly conserved multifunctional transcription factor that is involved in a variety of cellular processes. Many YY1-regulated genes have crucial roles in cell proliferation, differentiation, apoptosis, and cell cycle regulation. Numerous mechanisms have been shown to regulate the function of YY1, such as DNA binding affinity, subcellular localization, and posttranslational modification including phosphorylation. Polo-like kinase 1(Plk1) and Casein kinase 2α (CK2 α) were the first two kinases identified to phosphorylate YY1. In this study, we identify a third kinase. We report that YY1 is a novel substrate of the Aurora B kinase both in vitro and in vivo. Serine 184 phosphorylation of YY1 by Aurora B is cell cycle regulated and peaks at G2/M and is rapidly dephosphorylated, likely by protein phosphatase 1 (PP1) as the cells enter G1. Aurora A and Aurora C can also phosphorylate YY1 in vitro, but at serine/threonine residues other than serine 184. We present evidence that phosphorylation of YY1 in the central glycine/alanine (G/A)-rich region is important for DNA binding activity, with a potential phosphorylation/acetylation interplay regulating YY1 function. Given their importance in mitosis and overexpression in human cancers, Aurora kinases have been identified as promising therapeutic targets. Increasing our understanding of Aurora substrates will add to the understanding of their signaling pathways.

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Section: Introductionmentioning

confidence: 68%

Section: Introductionmentioning

confidence: 99%

The Transcription Factor YY1 Is a Novel Substrate for Aurora B Kinase at G2/M Transition of the Cell Cycle

et al. 2012

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“…Phosphorylation of threonine T58 at the P2 position in the caspase recognition motif by CKII or CKI prevents human Bid cleavage by caspase-8 (65). Phosphorylation of YY1 by CKII␣ prevents cleavage by caspase-7 during apoptosis (66). CKII phosphorylation during virus infection plays an important role in regulation of ICP27 and EB2 binding activities to cellular cofactors and promotes virus replication of HSV-1 and EBV (63,67,68).…”

Section: Discussionmentioning

confidence: 99%

Stability of Structured Kaposi's Sarcoma-Associated Herpesvirus ORF57 Protein Is Regulated by Protein Phosphorylation and Homodimerization

Majerčiak

Pripuzova

Chan

et al. 2015

J Virol

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Kaposi's sarcoma-associated herpesvirus (KSHV) ORF57 plays an essential role in KSHV lytic infection by promoting viral gene expression at the posttranscriptional level. Using bioinformatic and biochemical approaches, we determined that ORF57 contains two structurally and functionally distinct domains: a disordered nonstructural N-terminal domain (amino acids [aa] 1 to 152) and a structured ␣-helix-rich C-terminal domain (aa 153 to 455). The N-terminal domain mediates ORF57 interaction with several RNA-protein complexes essential for ORF57 to function. The N-terminal phosphorylation by cellular casein kinase II (CKII) at S21, T32, and S43, and other cellular kinases at S95 and S97 residues in proximity of the caspase-7 cleavage site, 30-DETD-33, inhibits caspase-7 digestion of ORF57. The structured C-terminal domain mediates homodimerization of ORF57, and the critical region for this function was mapped carefully to ␣-helices 7 to 9. Introduction of point mutations into ␣-helix 7 at ORF57 aa 280 to 299, a region highly conserved among ORF57 homologues from other herpesviruses, inhibited ORF57 homodimerization and led to proteasome-mediated degradation of ORF57 protein. Thus, homodimerization of ORF57 via its C terminus prevents ORF57 from degrading and allows two structure-free N termini of the dimerized ORF57 to work coordinately for host factor interactions, leading to productive KSHV lytic infection and pathogenesis. IMPORTANCEKSHV is a human oncogenic virus linked to the development of several malignancies. KSHV-mediated oncogenesis requires both latent and lytic infection. The KSHV ORF57 protein is essential for KSHV lytic replication, as it regulates the expression of viral lytic genes at the posttranscriptional level. This report provides evidence that the structural conformation of the ORF57 protein plays a critical role in regulation of ORF57 stability. Phosphorylation by CKII on the identified serine/threonine residues at the N-terminal unstructured domain of ORF57 prevents its digestion by caspase-7. The C-terminal domain of ORF57, which is rich in ␣-helices, contributes to homodimerization of ORF57 to prevent proteasome-mediated protein degradation. Elucidation of the ORF57 structure not only enables us to better understand ORF57 stability and functions but also provides an important tool for us to modulate ORF57's activity with the aim to inhibit KSHV lytic replication. K aposi's sarcoma-associated herpesvirus (KSHV) ORF57 (also known as Mta) is expressed early in the KSHV lytic cycle and is required for the efficient expression of a subset of viral genes, including KSHV PAN, ORF59, K8, viral interleukin-6 (vIL-6), ORF47, and others (1-7). A KSHV genome lacking ORF57 expression is associated with a defective lytic cycle incapable of producing infectious virions (8, 9).KSHV ORF57 functions as a posttranscriptional regulator of viral gene expression by affecting RNA stability (PAN, ORF59, and ORF47), splicing (ORF50 and K8), polyadenylation (ORF59), and translation (vIL-6) (1, 2, 4-7, 10) but ...

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“…2A) show that caspase substrates, including Bid, which promotes apoptotic progression when it is cleaved, can be phosphorylated by CSNK2 at sites adjacent to caspase cleavage sites. Because phosphorylation adjacent to caspase cleavage sites blocks cleavage, these observations suggest that increased phosphorylation by CSNK2 could promote cell survival by inhibiting caspase action (9)(10)(11)(12)(13)(14).…”

Section: Convergence Of Csnk2 With Caspase Pathwaysmentioning

confidence: 99%

Molecular Pathways: Emergence of Protein Kinase CK2 (CSNK2) as a Potential Target to Inhibit Survival and DNA Damage Response and Repair Pathways in Cancer Cells

Rabalski

Gyenis

Litchfield

2016

Clinical Cancer Research

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Protein kinase CK2 (designated CSNK2) is a constitutively active protein kinase with a vast repertoire of putative substrates that has been implicated in several human cancers, including cancer of the breast, lung, colon, and prostate, as well as hematologic malignancies. On the basis of these observations, CSNK2 has emerged as a candidate for targeted therapy, with two CSNK2 inhibitors in ongoing clinical trials. CX-4945 is a bioavailable small-molecule ATP-competitive inhibitor targeting its active site, and CIGB-300 is a cell-permeable cyclic peptide that prevents phosphorylation of the E7 protein of HPV16 by CSNK2. In preclinical models, either of these inhibitors exhibit antitumor efficacy. Furthermore, in combinations with chemotherapeutics such as cisplatin or gemcitabine, either CX-4945 or CIGB-300 promote synergistic induction of apoptosis. While CSNK2 is a regulatory participant in many processes related to cancer, its potential to modulate caspase action may be particularly pertinent to its emergence as a therapeutic target. Because the substrate recognition motifs for CSNK2 and caspases are remarkably similar, CSNK2 can block the cleavage of many caspase substrates through the phosphorylation of sites adjacent to cleavage sites. Phosphoproteomic strategies have also revealed previously underappreciated roles for CSNK2 in the phosphorylation of several key constituents of DNA damage and DNA repair pathways. Going forward, applications of proteomic strategies to interrogate responses to CSNK2 inhibitors are expected to reveal signatures for CSNK2 inhibition and molecular insights to guide new strategies to interfere with its potential to inhibit caspase action or enhance the susceptibility of cancer cells to DNA damage. Clin Cancer Res; 22(12); 2840-7. Ó2016 AACR. Disclosure of Potential Conflicts of InterestNo potential conflicts of interest were disclosed. Editor's DisclosuresThe following editor(s) reported relevant financial relationships: P.S. Steeg reports receiving commercial research grants from Genentech. CME Staff Planners' DisclosuresThe members of the planning committee have no real or apparent conflicts of interest to disclose. Learning ObjectivesUpon completion of this activity, the participant should have a better understanding of the role of protein kinase CK2 (CSNK2) in cellular processes that underlie malignancy, including its capacity to interfere with caspase action and involvement in DNA repair pathways, and the biological rationale of CSNK2 inhibitors as promising candidates for novel therapeutic strategies.

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Phosphorylation of the Transcription Factor YY1 by CK2α Prevents Cleavage by Caspase 7 during Apoptosis

Cited by 32 publications

References 70 publications

The Transcription Factor YY1 Is a Novel Substrate for Aurora B Kinase at G2/M Transition of the Cell Cycle

The Transcription Factor YY1 Is a Novel Substrate for Aurora B Kinase at G2/M Transition of the Cell Cycle

Stability of Structured Kaposi's Sarcoma-Associated Herpesvirus ORF57 Protein Is Regulated by Protein Phosphorylation and Homodimerization

Molecular Pathways: Emergence of Protein Kinase CK2 (CSNK2) as a Potential Target to Inhibit Survival and DNA Damage Response and Repair Pathways in Cancer Cells

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