Human herpesvirus 6B induces phosphorylation of p53 in its regulatory domain by a CK2- and p38-independent pathway

Øster, Bodil; Bundgaard, Bettina; Hupp, Ted R.; Höllsberg, Per

doi:10.1099/vir.0.83136-0

Cited by 21 publications

(23 citation statements)

References 55 publications

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“…CK1 Inhibitor Experiments-Mock-infected and HHV-6B-infected MOLT-3 cells were treated with 10 -100 M CK1 inhibitor D4476, concomitantly with infection, for 48 h. Alternatively, MOLT-3 cells were pretreated with 10 -60 M D4476 for 44 h before exposure (or sham exposure) to a 6-gray x-ray and further culture for 4 h. DMSO solvent controls were included, and cells were lysed as described previously (15).…”

Section: Methodsmentioning

confidence: 99%

“…1F6 and VC1 antibodies to VRK1 were generated as described previously (17). P-p53 Ser 15 antibody to p53 phosphorylated at Ser 15 and an antibody against CK1 were purchased from Cell Signaling Technology (supplied by New England Biolabs, Hitchin, UK). P-p53 Ser 20 antibody to p53 phosphorylated at Ser 20 and antibodies against CK1␣, CHK1, and CHK2 were obtained from Santa Cruz Biotechnology, Inc. (Santa Cruz, CA) (supplied by Insight Biotechnology, Wembley, UK).…”

Section: Methodsmentioning

confidence: 99%

“…It has been previously shown that human herpesvirus 6B (HHV-6B) infection of HCT116 and MOLT-3 cancer cell lines induced p53 phosphorylation (at Ser 15 , Ser 20 , Ser 33 , and Ser 392 ) and p53 accumulation in both nuclear and cytoplasmic fractions (14,15). It has also been shown that HHV-6B-infected cells were mostly nonapoptotic, and it has been suggested that in this context, p53 phosphorylation and accumulation may act as a survival factor rather than cell death inducer.…”

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confidence: 99%

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A Central Role for CK1 in Catalyzing Phosphorylation of the p53 Transactivation Domain at Serine 20 after HHV-6B Viral Infection

MacLaine

Øster

Bundgaard

et al. 2008

Journal of Biological Chemistry

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The tumor suppressor protein p53 is activated by distinct cellular stresses including radiation, hypoxia, type I interferon, and DNA/RNA virus infection. The transactivation domain of p53 contains a phosphorylation site at Ser 20 whose modification stabilizes the binding of the transcriptional co-activator p300 and whose mutation in murine transgenics induces B-cell lymphoma. Although the checkpoint kinase CHK2 is implicated in promoting Ser 20 site phosphorylation after irradiation, the enzyme that triggers this phosphorylation after DNA viral infection is undefined. Using human herpesvirus 6B (HHV-6B) as a virus that induces Ser 20 site phosphorylation of p53 in T-cells, we sought to identify the kinase responsible for this virus-induced p53 modification. The p53 Ser 20 kinase was fractionated and purified using cation, anion, and dye-ligand exchange chromatography. Mass spectrometry identified casein kinase 1 (CK1) and vaccinia-related kinase 1 (VRK1) as enzymes that coeluted with virus-induced Ser 20 site kinase activity. Immunodepletion of CK1 but not VRK1 removed the kinase activity from the peak fraction, and bacterially expressed CK1 exhibited Ser 20 site kinase activity equivalent to that of the virus-induced native CK1. CK1 modified p53 in a docking-dependent manner, which is similar to other known Ser 20 site p53 kinases. Low levels of the CK1 inhibitor D4476 selectively inhibited HHV-6B-induced Ser 20 site phosphorylation of p53. However, x-ray-induced Ser 20 site phosphorylation of p53 was not blocked by D4476. These data highlight a central role for CK1 as the Ser 20 site kinase for p53 in DNA virus-infected cells but also suggest that distinct stresses may selectively trigger different protein kinases to modify the transactivation domain of p53 at Ser 20 .The tumor suppressor protein p53 is a key player in the survival or death decision that cells face after exposure to a variety of metabolic and genotoxic stresses (1). The transient accumulation and activation of p53 in response to various cellular stresses enables the protein to modulate the expression of numerous genes involved in cell cycle arrest, DNA repair, and/or apoptosis. The initiation of either transient cell cycle arrest and damage repair or apoptosis is dependent on the cell and damage type, the severity of damage, and the cellular microenvironment. Phosphorylation and acetylation events that control interactions between the transcription factor p53 and its negative regulators (Mdm2, COP1, and Pirh2) or coactivators (p300) are ultimately involved in modulating p53-dependent gene expression in response to cellular stress (2). In particular, phosphorylation at Thr 18 within the N-terminal conserved BOX-I domain of p53 blocks the binding of Mdm2, whereas phosphorylation at Ser 20 , also within the BOX-I domain, enables the binding of p300 (3-5). Thus, phosphorylation in this transactivation domain serves to stimulate rather than inhibit p53 function. In addition, phosphorylation at Ser 392 within the C terminus of p53 stimulates the seq...

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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A Central Role for CK1 in Catalyzing Phosphorylation of the p53 Transactivation Domain at Serine 20 after HHV-6B Viral Infection

MacLaine

Øster

Bundgaard

et al. 2008

Journal of Biological Chemistry

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“…Much is known about the mechanisms by which viral proteins in transformed cells prevent the activities of p53 (12). During infection, HHV-6B induces significant accumulation of p53 in both the nucleus and cytoplasm, and determines phosphorylation of p53 at Ser392 (13)(14)(15). TP53 restricts the production of HHV-6B mRNAs and proteins, which inhibits viral replication and diminishes the cytopathic effects of the virus (16).…”

Section: Introductionmentioning

confidence: 99%

Herpesvirus type 7 infection may play an important role in individuals with a genetic profile of susceptibility to Graves' disease

Leite

Bufalo²,

Santos³

et al. 2010

European Journal of Endocrinology

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Objective: An inherited profile of genes related to the response to aggressive environmental factors such as viruses and chemicals may be related to an increased susceptibility to Graves' disease (GD). Design and methods: This prospective case-control study was designed to examine the relationship between human herpesviruses (HHV) infection, determined by circulating DNA; tumour protein p53 (TP53) apoptotic ability; and detoxification system genes, and GD. We studied 280 confirmed GD patients paired to 284 controls with respect to environmental exposure. Exclusion criteria included medications that could interfere with thyroid function evaluation and a recent history of viral and bacterial infections. Results: A stepwise regression analysis adjusted for age, gender, and ethnicity established the inheritance of glutathione S-transferase pi 1 (GSTP1) (odds ratio (OR)Z3.423; 95% confidence interval (CI)Z2.120-5.527; P!0.001) and cytochrome P450, family 1, subfamily A, polypeptide 1 (CYP1A1) variants (ORZ1.649; 95% CIZ1.012-2.686; PZ0.0445) as significant risk factors for the disease. HHV-7 infection was much more common in GD patients (64.64%) than in controls (38.73%; c 2 , P!0.0001), and it increased the risk for GD more than three times (ORZ3.133; 95% CIZ1.959-5.011; P!0.0001). The inheritance of less efficient Pro/Pro TP53 gene variants significantly increased the risk of GD development (ORZ5.196;; P!0.0001) and also favored HHV-7 infection (ORZ2.835; 95% CIZ1.100-7.310; PZ0.0275). In addition, 72TP53 variants augmented the risk of GD relapse (ORZ1.860; 95% CIZ1.015-3.410; PZ0.0446). Conclusions: We suggest that an inherited genetic profile involving TP53 may favor HHV-7 infection and maintenance, which, in turn, may initiate and perpetuate GD autoimmune process.

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“…Although it remains to be determined, in RT4 cells, one (or more) of the ATM, ATR and DNA-PK kinases could be likely implicated in the cisplatin-induced phosphorylation of p53 at Ser15, whereas Ser392 phosphorylation might be implemented by one (or more) of the p38 MAPK, CDK9 and CK2 kinases (65)(66)(67). Accordingly, a role of ATR/Chk2 signaling in p53 activation and subsequent apoptosis has been recently demonstrated in cisplatin-treated renal cells, thereby further illuminating the drug-induced nephrotoxicity mechanisms (15).…”

Section: Discussionmentioning

confidence: 99%

Human bladder cancer cells undergo cisplatin-induced apoptosis that is associated with p53-dependent and p53-independent responses

Konstantakou

Voutsinas²,

Karkoulis³

et al. 2009

Int J Oncol

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Abstract.Cisplatin is a first-line chemotherapeutic agent and a powerful component of standard treatment regimens for several human malignancies including bladder cancer. DNAPt adducts produced by cisplatin are mainly responsible for cellular toxicity and induction of apoptosis. Identification of the mechanisms that control sensitivity to cisplatin is central to improving its therapeutic index and to successfully encountering the acquired resistance frequently emerging during therapy. In the present study, using MTT-based assays, Western blotting and semi-quantitative RT-PCR, we examined the apoptosis-related cellular responses to cisplatin exposure in two human urinary bladder cancer cell lines characterized by different malignancy grade and p53 genetic status. Both RT4 (grade I; wild-type p53) and T24 (grade III; mutant p53) cell types proved to be vulnerable to cisplatin apoptotic activity, albeit in a grade-dependent and drug dose-specific manner, as demonstrated by the proteolytic processing profiles of Caspase-8, Caspase-9, Caspase-3, and the Caspase repertoire characteristic substrates PARP and Lamin A/C, as well. The differential resistance of RT4 and T24 cells to cisplatin-induced apoptosis was associated with an RT4-specific phosphorylation (Ser15; Ser392) pattern of p53, together with structural amputations of the Akt and XIAP anti-apoptotic regulators. Furthermore, cisplatin administration resulted in a Granzyme B-mediated proteolytic cleavage of Hsp90 molecular chaperone, exclusively occurring in RT4 cells. To generate functional networks, expression analysis of a number of genes, including Bik, Bim, Fas, FasL, TRAIL, Puma, ATP7A, ATP7B and MRP1, was performed, strongly supporting the role of p53-dependent and p53-independent transcriptional responses in cisplatin-induced apoptosis of bladder cancer cells. IntroductionWith its incidence continuing to increase, bladder cancer is classified among the five most common malignancies in industrialized countries (1). Forming a worldwide estimate over one million patients, bladder cancer is clearly considered a significant public health issue around the world (2). The three main types of cancer affecting bladder are transitional cell carcinoma (TCC), squamous cell carcinoma (SCC) and adenocarcinoma (ADC), with TCC representing >90% of all bladder cancers. Four clinically distinct entities of TCC have been recognized: superficial, papillary tumors (Ta and T1), carcinoma in situ (Tis), muscle-invasive tumors (T2-T4) and advanced disease, involving extra-pelvic nodal or distant metastasis (3,4). Metastatic TCC demonstrates a moderate sensitivity to chemotherapy while a significant variation in patient survival rates and activity levels of individual regimens has been observed (5).Cisplatin-based combination chemotherapy protocols, such as MVAC (methotrexate-vinblastine-adriamycin-cisplatin), constituted for a number of years standard treatment of patients with advanced (or metastatic) urothelial bladder cancer. However, due to the MVAC-induced systemic toxici...

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Human herpesvirus 6B induces phosphorylation of p53 in its regulatory domain by a CK2- and p38-independent pathway

Cited by 21 publications

References 55 publications

A Central Role for CK1 in Catalyzing Phosphorylation of the p53 Transactivation Domain at Serine 20 after HHV-6B Viral Infection

A Central Role for CK1 in Catalyzing Phosphorylation of the p53 Transactivation Domain at Serine 20 after HHV-6B Viral Infection

Herpesvirus type 7 infection may play an important role in individuals with a genetic profile of susceptibility to Graves' disease

Human bladder cancer cells undergo cisplatin-induced apoptosis that is associated with p53-dependent and p53-independent responses

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