Immune Defects in 28-kDa Proteasome Activator γ-Deficient Mice

Barton, Lance F.; Runnels, Herbert A.; Schell, Todd D.; Cho, Yunjung; Gibbons, Reta; Tevethia, Satvir S.; Deepe, George S.; Monaco, John J.

doi:10.4049/jimmunol.172.6.3948

Cited by 106 publications

(119 citation statements)

References 47 publications

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“…In addition, REG␥ Ϫ/Ϫ mouse embryonic fibroblasts show slow growth and accumulation in the S phase and are more susceptible to apoptosis (48,49). The biological role of REG␥ in cell cycle regulation and cell survival is underlined by these observations.…”

Section: Htlv-1 P30mentioning

confidence: 72%

Human T-lymphotropic Virus Type 1 p30 Interacts with REGγ and Modulates ATM (Ataxia Telangiectasia Mutated) to Promote Cell Survival

Anupam¹,

Datta²,

Kesic³

et al. 2011

Journal of Biological Chemistry

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Human T-lymphotropic virus type 1 (HTLV-1) is a causative agent of adult T cell leukemia/lymphoma and a variety of inflammatory disorders. HTLV-1 encodes a nuclear localizing protein, p30, that selectively alters viral and cellular gene expression, activates G 2 -M cell cycle checkpoints, and is essential for viral spread. Here, we used immunoprecipitation and affinity pulldown of ectopically expressed p30 coupled with mass spectrometry to identify cellular binding partners of p30. Our data indicate that p30 specifically binds to cellular ATM (ataxia telangiectasia mutated) and REG␥ (a nuclear 20 S proteasome activator). Under conditions of genotoxic stress, p30 expression was associated with reduced levels of ATM and increased cell survival. Knockdown or overexpression of REG␥ paralleled p30 expression, suggesting an unexpected enhancement of p30 expression in the presence of REG␥. Finally, size exclusion chromatography revealed the presence of p30 in a high molecular mass complex along with ATM and REG␥. On the basis of our findings, we propose that HTLV-1 p30 interacts with ATM and REG␥ to increase viral spread by facilitating cell survival. Human T-lymphotropic virus type 1 (HTLV-1)2 is a complex deltaretrovirus and the first reported human retrovirus linked to malignancy (1, 2). It is estimated that ϳ20 million people worldwide are infected with HTLV-1 (3). Approximately five percent of these infected individuals will develop one of a variety of immunopathologic or neoplastic conditions (reviewed in Ref. 4). Two well characterized pathological conditions associated with HTLV-1 infection are adult T cell leukemia/lymphoma, a highly aggressive T cell malignancy, and HTLV-1-associated myelopathy/tropical spastic paraparesis, an immune-mediated neurodegenerative condition (5, 6). The prolonged latency between acquisition of infection and disease expression indicates a highly regulated host-virus relationship that promotes survival of HTLV-1-infected cell reservoirs.HTLV-1 contains genes that encode typical retroviral structural and enzymatic proteins such as Gag, Pol, and Env, as well as regulatory proteins Tax and Rex (reviewed in Ref. 4). The pX region of HTLV-1 contains open reading frames that also encode for various nonstructural proteins (p12, p13, HBZ, and p30) that are essential to viral transmission and spread (7-12).HTLV-1 p30 is a nuclear and nucleolar localizing protein encoded by a doubly spliced mRNA from ORF II of the pX region of the viral genome (13, 14) that modulates viral and cellular gene expression by transcriptional and post-translational mechanisms (14, 15). HTLV-1-infected individuals produce cytotoxic T cells and antibodies to p30 peptides (16,17). We reported that p30 differentially modulates the activity of HTLV-1 promoter-driven reporter genes (18) through its interaction with the transcriptional coactivator p300 (19). In Jurkat T cells, p30 alters the expression of a variety of cellular genes and also enhances signal pathways important for T cell growth and survival (20). Ectopical...

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Section: Htlv-1 P30mentioning

confidence: 72%

Human T-lymphotropic Virus Type 1 p30 Interacts with REGγ and Modulates ATM (Ataxia Telangiectasia Mutated) to Promote Cell Survival

Anupam¹,

Datta²,

Kesic³

et al. 2011

Journal of Biological Chemistry

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“…REGg -/-mice with C57BL/6 genetic background were acquired from Dr John J. Monaco 38 and bred in the Animal Core Facility following procedures approved by the Institutional Animal Care and Use Committee. Genotyping of REGg þ / þ and REGg -/-mice was carried out by PCR analysis of genomic DNA as described previously 16 .…”

Section: Methodsmentioning

confidence: 99%

REGγ is critical for skin carcinogenesis by modulating the Wnt/β-catenin pathway

Dang

Zhang

et al. 2015

Nat Commun

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Here we report that mice deficient for the proteasome activator, REGg, exhibit a marked resistance to TPA (12-O-tetradecanoyl-phorbol-13-acetate)-induced keratinocyte proliferation, epidermal hyperplasia and onset of papillomas compared with wild-type counterparts. Interestingly, a massive increase of REGg in skin tissues or cells resulting from TPA induces activation of p38 mitogen-activated protein kinase (MAPK/p38). Blocking p38 MAPK activation prevents REGg elevation in HaCaT cells with TPA treatment. AP-1, the downstream effector of MAPK/p38, directly binds to the REGg promoter and activates its transcription in response to TPA stimulation. Furthermore, we find that REGg activates Wnt/b-catenin signalling by degrading GSK-3b in vitro and in cells, increasing levels of CyclinD1 and c-Myc, the downstream targets of b-catenin. Conversely, MAPK/p38 inactivation or REGg deletion prevents the increase of cyclinD1 and c-Myc by TPA. This study demonstrates that REGg acts in skin tumorigenesis mediating MAPK/p38 activation of the Wnt/b-catenin pathway.

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“…Although the functional significance of REGγ has not been fully defined, previous studies suggest a role for REGγ in the regulation of cell cycle progression and apoptosis. REGγ-deficient mice showed reduced body size and defects in cell-specific mitosis (Murata et al, 1999;Barton et al, 2004). Moreover, the expression of REGγ has been found abnormally high in human breast cancer cells and the metastatic lymph nodes (Wang et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Expression of Proteasome Activator REGγ in Human Laryngeal Carcinoma and Associations with Tumor Suppressor Proteins

Cheng²,

Li³

et al. 2012

Asian Pacific Journal of Cancer Prevention

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The functional significance of the proteasome activator REGγ in the regulation of cell proliferation and apoptosis has been recognized. However, pathological contributions to tumor development remain to be elucidated. Both oncogenic proteins and tumor suppressors are targeted by REGγ for proteasomal degradation. It has been proposed that the role of the REGγ in the pathogenesis of cancer is cell-and context-specific. In this study, we aimed to explore the potential involvement of REGγ in laryngeal carcinomas, comparing protein expression in tumor and adjacent tissues by immunohistochemical staining and Western blot analysis. We also characterized the correlation between the expression of REGγ and the previously identified substrates p53 and p21. We showed that REGγ was abnormally highly expressed in cancer tissues. Statistical analysis revealed that there was a positive relationship between the level of REGγ and the expression of p53 and p21. Our study suggests that REGγ overexpression can facilitate the growth of laryngeal cancer cells.

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Immune Defects in 28-kDa Proteasome Activator γ-Deficient Mice

Cited by 106 publications

References 47 publications

Human T-lymphotropic Virus Type 1 p30 Interacts with REGγ and Modulates ATM (Ataxia Telangiectasia Mutated) to Promote Cell Survival

Human T-lymphotropic Virus Type 1 p30 Interacts with REGγ and Modulates ATM (Ataxia Telangiectasia Mutated) to Promote Cell Survival

REGγ is critical for skin carcinogenesis by modulating the Wnt/β-catenin pathway

Expression of Proteasome Activator REGγ in Human Laryngeal Carcinoma and Associations with Tumor Suppressor Proteins

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