Human Cytomegalovirus IE1-72 Protein Interacts with p53 and Inhibits p53-Dependent Transactivation by a Mechanism Different from That of IE2-86 Protein

Hwang, Eung Soo; Zhang, Zhigang; Cai, Hao; Huang, David; Huong, Shu-Mei; Cha, Chang-Yong; Huang, Eng‐Shang

doi:10.1128/jvi.00304-09

Cited by 48 publications

(42 citation statements)

References 81 publications

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“…Finally, the viral proteins pUL25, pUL84, and pUL38 were observed. HCMV pUL84 has been previously demonstrated to associate with p53, the NuRD component RBBP4, and importin ␣ (Table 1) (42,63,64). Our results suggest that pUL29/28 interacts with multiple viral and cellular proteins at 24 hpi, including the tumor suppressor protein p53.…”

Section: Hcmv Pul29/28 Interacts With Cellular P53 During Infectionsupporting

confidence: 49%

“…This indicates a role for other HCMV proteins in regulating p53. Studies completed by several laboratories have demonstrated the involvement of the immediate early proteins IE1 (pUL123) and IE2 (pUL122) in regulating p53 activities (22,35,(39)(40)(41)(42)44). Furthermore, pUL84 and pUL44 have also been implicated (42,43).…”

Section: Discussionmentioning

confidence: 99%

“…Studies completed by several laboratories have demonstrated the involvement of the immediate early proteins IE1 (pUL123) and IE2 (pUL122) in regulating p53 activities (22,35,(39)(40)(41)(42)44). Furthermore, pUL84 and pUL44 have also been implicated (42,43). One challenge that we faced in these studies was distinguishing between the role of pUL29/28 in 18 h, or infected with ADwt or ADdel29 at an MOI of 6 for 18 h. Chromatin immunoprecipitation (ChIP) was performed using an antibody against pan-p53 or control IgG.…”

Section: Discussionmentioning

confidence: 99%

“…Reevaluation of expression changes in known p53-responsive genes (37) from microarray studies on HCMV infected cells (38) identified only 8 genes that increased in expression at multiple times postinfection, while 61 decreased or did not change within the first 24 h postin-fection (hpi) (see Table S1 in the supplemental material). The HCMV proteins IE1, IE2, pUL44, and pUL84 participate in regulating p53 by binding to and altering p53-mediated transcription (22,35,(39)(40)(41)(42)(43)(44). In addition, regulation of p53 is partially achieved by relocalization of a subpopulation of p53 to viral replication centers within the nucleus (17).…”

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confidence: 99%

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Human Cytomegalovirus pUL29/28 and pUL38 Repression of p53-Regulated p21CIP1 and Caspase 1 Promoters during Infection

Savaryn

Reitsma

Bigley

et al. 2013

J Virol

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c During infection by human cytomegalovirus (HCMV), the tumor suppressor protein p53, which promotes efficient viral gene expression, is stabilized. However, the expression of numerous p53-responsive cellular genes is not upregulated. The molecular mechanism used to manipulate the transcriptional activity of p53 during infection remains unclear. The HCMV proteins IE1, IE2, pUL44, and pUL84 likely contribute to the regulation of p53. In this study, we used a discovery-based approach to identify the protein targets of the HCMV protein pUL29/28 during infection. Previous studies have demonstrated that pUL29/28 regulates viral gene expression by interacting with the chromatin remodeling complex NuRD. Here, we observed that pUL29/28 also associates with p53, an additional deacetylase complex, and several HCMV proteins, including pUL38. We confirmed the interaction between p53 and pUL29/28 in both the presence and absence of infection. HCMV pUL29/28 with pUL38 altered the activity of the 53-regulatable p21CIP1 promoter. During infection, pUL29/28 and pUL38 contributed to the inhibition of p21CIP1 as well as caspase 1 expression. The expression of several other p53-regulating genes was not altered. Infection using a UL29-deficient virus resulted in increased p53 binding and histone H3 acetylation at the responsive promoters. Furthermore, expression of pUL29/28 and its interacting partner pUL38 contributed to an increase in the steady-state protein levels of p53. This study identified two additional HCMV proteins, pUL29/28 and pUL38, which participate in the complex regulation of p53 transcriptional activity during infection. Human cytomegalovirus (HCMV) is a member of the betaherpesvirus family, which also includes human herpesviruses 6 and 7. Infection by HCMV is a leading cause of birth defects and can cause severe disease upon immunosuppression (reviewed in reference 1). HCMV disease in immunosuppressed individuals is often successfully managed using the antiviral compound ganciclovir, valganciclovir, cidofovir, or foscarnet. Congenital HCMV infection, however, remains a significant problem because of limited diagnostics and treatment options as well as the lack of community awareness (2). The initial infection leads to systemic viral spread and a balance between latent and lytic replication cycles among diverse cell types within the body. These complex replication cycles result in a persistent lifelong infection.Successful HCMV infection involves viral proteins interacting with and disconnecting cellular stress response pathways. Many of these pathways and the associated proteins are also altered in cancers and are conserved targets among diverse herpesviruses. Examples include DAXX (death domain-associated protein) (3-6), PML (promyelocytic leukemia protein) (7-11), IFI16 (interferoninducible protein 16) (12, 13), Tip60 (Tat-interactive protein, 60 kDa) (14, 15), and p53 (16-24). Upon infection, delivery of the HCMV tegument protein pp71 (UL82) results in the degradation of cellular DAXX and disruption of an intri...

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Section: Hcmv Pul29/28 Interacts With Cellular P53 During Infectionsupporting

confidence: 49%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Human Cytomegalovirus pUL29/28 and pUL38 Repression of p53-Regulated p21CIP1 and Caspase 1 Promoters during Infection

Savaryn

Reitsma

Bigley

et al. 2013

J Virol

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“…HCMV IE2-86 protein can reduce transcriptional activity of p53 by 297 Original Article the direct interaction with it and result in a cellular proliferation, which might involve in the restenosis of coronary artery after surgery (12). Our previous studies show HCMV IE1-72 and UL44 also inhibit p53-dependent transcription in different ways (13,14). Besides transcriptional regulation p53 facilitates the transportation of one of HCMV matrix proteins from nucleus to cytoplasm and induces the production of viruses (15).…”

Section: Introductionmentioning

confidence: 99%

Cytoplasmic Translocation of p53 by Human Cytomegalovirus Infection

Kwon

Kim

et al. 2013

J Bacteriol Virol

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p53 is a well-known multi-functional transcription regulator and is critical in the induction of apoptosis in response to various stresses. Human cytomegalovirus (HCMV) infection induced the accumulation of p53, which was partly relocalized in cytoplasm, but no apparent cell death in human fibroblasts. p53 in HCMV-infected cells was mainly mono-ubiquitinated, which might be resulted from the decreased expression of MDM2 in the course of HCMV infection. Ubiquitinated p53 was also phosphorylated at serine 20. CRM1 increased in the cytoplasm of HCMV-infected cells. It was found that p53 and its mutant in nuclear export sequences were localized in the cytoplasm of cells when co-expressed with CRM1. Collectively, our data suggest that HCMV infection modifies p53 into a stable and exportable form and accumulates it in the cytoplasm, but does not result in apoptotic death of cells.

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