Pirh2 interacts with and ubiquitylates signal recognition particle receptor β subunit

Abe, Kenji; Hattori, Takayuki; Isobe, Tomoyasu; Kitagawa, Kyoko; Oda, Toshiaki; Uchida, Chiharu; Kitagawa, Masatoshi

doi:10.2220/biomedres.29.53

Cited by 7 publications

(5 citation statements)

References 23 publications

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“…To validate their interaction, we first detected the subcellular locations of Tas and Pirh2 by transfecting pEGFP-C1-Tas or pDsRed-N1-Pirh2 into 293T cells for 24 h, to investigate whether they would change the distribution by co-expressing with each other, 293T cells were also cotransfected with pEGFP-C1-Tas and pDsRed-N1-Pirh2 for 24 h, and examining the transfected cells with an Olympus confocal microscope. The distribution of Tas was almost completely nuclear, while, Pirh2 was distributed throughout both the nucleus and the cytoplasm, as reported previously [ 29 ], and they colocalized predominantly in the nucleus and the co-expression did not change their distribution in the cells ( Figure 1 A). To further confirm the interaction between Tas and Pirh2, coimmunoprecipitation was performed by co-transfecting 293T cells with myc-Tas and Flag-Pirh2.…”

Section: Resultssupporting

confidence: 87%

Human Pirh2 is A Novel Inhibitor of Prototype Foamy Virus Replication

Dong

Cheng

Wang

et al. 2015

Viruses

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Prototype foamy virus (PFV) is a member of the unconventional and nonpathogenic retroviruses. PFV causes lifelong chronic infections, which are partially attributable to a number of host cell factors that restrict viral replication. Herein, we identified human p53-induced RING-H2 protein (Pirh2) as a novel inhibitor of prototype foamy virus. Overexpression of Pirh2 decreased the replication of PFV, whereas knockdown of Pirh2 with specific siRNA increased PFV replication. Dual-luciferase assays and coimmunoprecipitation demonstrated that Pirh2 negatively influences the Tas-dependent transcriptional activation of the PFV long terminal repeat (LTR) and internal promoter (IP) by interacting with the transactivator Tas and down-regulating its expression. In addition, the viral inhibitory function of Pirh2 is N-terminal and RING domain dependent. Together, these results indicated that Pirh2 suppresses PFV replication by negatively impacting its transactivator Tas and the transcription of two viral promoters, which may contribute to the latency of PFV infection.

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Section: Resultssupporting

confidence: 87%

Human Pirh2 is A Novel Inhibitor of Prototype Foamy Virus Replication

Dong

Cheng

Wang

et al. 2015

Viruses

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“…In contrast to p53, p27 mutations in human tumors are extremely rare. ( 20 ) Although several targets for Pirh2 have been reported, such as p53, androgen receptor, ɛ‐COP (epsilon‐subunit of coatmer complex), and SR‐β (signal recognition particle receptor beta subunit), ( 9,21–23 ) because p27 level reverse‐correlates with Pirh2 expression, p27 may be an important target of Pirh2 in human cancers.…”

Section: Discussionmentioning

confidence: 99%

High expression of Pirh2, an E3 ligase for p27, is associated with low expression of p27 and poor prognosis in head and neck cancers

Shimada

Kitagawa²,

Dobashi

et al. 2009

Cancer Science

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Downregulation of the cyclin-dependent kinase inhibitory protein p27 is frequently observed in various cancers due to enhancement of its degradation. We recently reported that p53-inducible protein with RING-H2 domain (Pirh2) is a novel ubiquitin ligase for p27, required for the ubiquitylation and consequent degradation of p27 protein. However, there is no reports about the involvement of Pirh2 in both p27 downregulation and pathogenesis in human cancers. In the present study, we investigated them using cultured cell lines and surgical specimens derived from human head and neck squamous cell carcinoma (HNSCC). Depletion of Pirh2 by short interfering RNA induced accumulation of p27 and inhibited the growth of cultured HNSCC cells. By immunohistochemical analysis in 57 cases of HNSCC specimens, higher levels of Pirh2 expression (labeling index ³ 60%) were found in 61.4% of HNSCC in comparison with 0% of normal mucosa. In addition, 83.3% of HNSCC with lower p27 expression (labeling index < 20%) displayed high Pirh2 levels. Therefore, Pirh2 expression was inversely correlated with p27 expression. Finally, Pirh2 expression was well correlated with poor prognosis. These findings suggest that Pirh2 overexpression may have an important role in the development and maintenance of HNSCC at least partially through p27 degradation, and that Pirh2 may be a potential molecular target for human HNSCC. (Cancer Sci 2009; 100: 866-872)

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“…Interestingly, some of the E3 ligases important for the regulation of c-Myc also regulate p53 function. SKP2 negatively regulates p53 by suppressing its acetylation by p300 while ARF-BP1 suppresses p53 through its polyubiquitylation and proteolysis [8], [9]. Furthermore, FBW7 loss of function has been reported to attenuate p53 activity [10].…”

Section: Introductionmentioning

confidence: 99%

Role of Pirh2 in Mediating the Regulation of p53 and c-Myc

et al. 2011

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Ubiquitylation is fundamental for the regulation of the stability and function of p53 and c-Myc. The E3 ligase Pirh2 has been reported to polyubiquitylate p53 and to mediate its proteasomal degradation. Here, using Pirh2 deficient mice, we report that Pirh2 is important for the in vivo regulation of p53 stability in response to DNA damage. We also demonstrate that c-Myc is a novel interacting protein for Pirh2 and that Pirh2 mediates its polyubiquitylation and proteolysis. Pirh2 mutant mice display elevated levels of c-Myc and are predisposed for plasma cell hyperplasia and tumorigenesis. Consistent with the role p53 plays in suppressing c-Myc-induced oncogenesis, its deficiency exacerbates tumorigenesis of Pirh2−/− mice. We also report that low expression of human PIRH2 in lung, ovarian, and breast cancers correlates with decreased patients' survival. Collectively, our data reveal the in vivo roles of Pirh2 in the regulation of p53 and c-Myc stability and support its role as a tumor suppressor.

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Pirh2 interacts with and ubiquitylates signal recognition particle receptor β subunit

Abstract: Pirh2 is a RING finger type ubiquitin ligase which ubiquitylates various proteins including p53, p27Kip1

Cited by 7 publications

References 23 publications

Human Pirh2 is A Novel Inhibitor of Prototype Foamy Virus Replication

Human Pirh2 is A Novel Inhibitor of Prototype Foamy Virus Replication

High expression of Pirh2, an E3 ligase for p27, is associated with low expression of p27 and poor prognosis in head and neck cancers

Role of Pirh2 in Mediating the Regulation of p53 and c-Myc

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