Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Murine PIRH2 (mPIRH2) was recently identified as a RING finger-containing ubiquitin-protein isopeptide ligase that interacts with both p53 and the human androgen receptor. mpirh2 is a p53-responsive gene that is up-regulated by UV, and mPIRH2 protein has the capacity to polyubiquitylate p53, perhaps leading to p53 destruction. mpirh2 therefore has properties similar to those of the oncogene mdm2. Here, we have identified human PIRH2 (hPIRH2) as a TIP60-interacting protein. To investigate its regulation, we characterized hPIRH2 in parallel with hPIRH2 variants possessing mutations of conserved RING finger residues. We observed that wild-type hPIRH2 is an unstable protein with a short half-life and is a target for RING domain-dependent proteasomal degradation. Accordingly, we found that hPIRH2 was ubiquitylated in cells. The TIP60-hPIRH2 association appeared to regulate hPIRH2 stability; coexpression of TIP60 enhanced hPIRH2 protein stability and altered hPIRH2 subcellular localization. These results suggest that hPIRH2 activities can be controlled, at the post-translational level, in multiple ways.
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PMID:Control of human PIRH2 protein stability: involvement of TIP60 and the proteosome. 1470 4

Using a C-terminal domain (PCT) of the measles virus (MV) phosphoprotein (P protein) as bait in a yeast two-hybrid screen, a cDNA identical to the recently described human p53-induced-RING-H2 (hPIRH2) cDNA was isolated. A glutathione S-transferase-hPIRH2 fusion protein expressed in bacteria was able to pull down P protein when mixed with an extract from P-expressing HeLa cells in vitro, and myc-tagged hPIRH2 could be reciprocally co-immunoprecipitated with MV P protein from human cells. Additionally, immunoprecipitation experiments demonstrated that hPIRH2-myc, MV P, and nucleocapsid (N) proteins form a ternary complex. The hPIRH2 binding site was mapped to the C-terminal X domain region of the P protein by using a yeast two-hybrid assay. The PCT binding site was mapped on hPIRH2 by using a novel yeast two-hybrid tagged PCR approach and by co-immunoprecipitation of hPIRH2 cysteine mutants and mouse/human PIRH2 chimeras. The hPIRH2 C terminus could mediate the interaction with MV P which was favored by the RING-H2 motif. When coexpressed with an enhanced green fluorescent protein-tagged hPIRH2 protein, MV P alone or in a complex with MV N was able to redistribute hPIRH2 to outside the nucleus, within intracellular aggregates. Finally, MV P efficiently stabilized hPIRH2-myc expression and prevented its ubiquitination in vivo but had no effect on the stability or ubiquitination of an alternative ubiquitin E3 ligase, Mdm2. Thus, MV P protein is the first protein from a pathogen that is able to specifically interact with and stabilize the ubiquitin E3 ligase hPIRH2 by preventing its ubiquitination.
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PMID:Inhibition of ubiquitination and stabilization of human ubiquitin E3 ligase PIRH2 by measles virus phosphoprotein. 1614 Jul 59

Ubiquitylation appears to be involved in the membrane trafficking system including endocytosis, exocytosis, and ER-to-Golgi transport. We found that PIRH2, which was identified as an interacting protein for androgen receptor or p53, interacts with and ubiquitylates the epsilon-subunit of coatmer complex, epsilon-COP. PIRH2 promotes the ubiquitylation of epsilon-COP in vitro and in vivo and consequently promotes the degradation of epsilon-COP. The interaction between PIRH2 and epsilon-COP is affected by the presence of androgen, and PIRH2 in the presence of androgen promotes ubiquitylation of epsilon-COP in vivo. Furthermore, overexpression of the wild type of PIRH2 in prostate cancer cells causes downregulation of the secretion of prostate-specific antigen (PSA), a secretory protein in prostate epithelial cells and one of diagnostic markers for prostate cancer. Our results indicate that PIRH2 functions as a regulator for COP I complex.
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PMID:Ubiquitylation of epsilon-COP by PIRH2 and regulation of the secretion of PSA. 1772 9

PLAGL2 (Pleomorphic Adenoma Gene Like 2) is an oncoprotein involved in various malignancies including lipoblastomas, hepatoblastomas, and acute myeloid leukemia. Although PLAGL2 is known to mainly act as a transcription factor, other functions which may contribute to its oncogenic potential are not clear. Pirh2 (P53 induced RING-H2 protein) is a p53 inducible E3 ligase involved in the ubiquitination of p53, while the mechanisms to regulate its activities are largely unknown. In this study, we show for the first time that Pirh2 forms dimers through its N- and C-terminus in cells and Pirh2 dimers interact with PLAGL2. The interaction between PLAGL2 and Pirh2 dimers prevents proteasomal degradation of Pirh2. This study thus uncovers a novel function of PLAGL2 as an oncoprotein through regulating the stability of Pirh2. Given the importance of Pirh2 in regulating p53 stability, its interaction with PLAGL2 may provide valuable therapeutic targets in treating Pirh2-overexpression malignancies.
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PMID:PLAGL2 controls the stability of Pirh2, an E3 ubiquitin ligase for p53. 1795 Feb 44

Most of the p53 target genes, all except MDM2, COP1 and PIRH2, perform functions in apoptosis, differentiation and cell cycle arrest. The aforementioned oncogenes downregulate p53 through a negative feedback mechanism, and thus contribute to tumor development. In this study, we report a new p53 target, PRL-1, which is believed to be a significant regulator in the development and metastasis of a variety of cancer types. Phosphatase of regenerating liver 1 (PRL-1) overexpression reduced the levels of endogenous and exogenous p53 proteins, and inhibited p53-mediated apoptosis. On the other hand, the ablation of PRL-1 by small interfering RNA (siRNA) increased p53 protein levels. The p53 downregulation was mediated by p53 ubiquitination and subsequent proteasomal degradation. Furthermore, p53 ubiquitination by PRL-1 was achieved through two independent pathways, by inducing PIRH2 transcription and by inducing MDM2 phosphorylation through Akt signaling. In addition, we showed that the PRL-1 gene harbors a p53 response element in the first intron, and its transcription is regulated by the p53 protein. These findings imply that the new oncogenic p53 target, PRL-1, may contribute to tumor development by the downregulation of p53 by a negative feedback mechanism.
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PMID:New p53 target, phosphatase of regenerating liver 1 (PRL-1) downregulates p53. 1899 16

A novel splice variant of hPirh2, named hPirh2b, was isolated from human fetal liver cDNA library. hPirh2b has a 38-nucleotide deletion and encodes a 188-amino acid protein with a truncated RING-H2 domain. It shows no ubiquitin protein ligase activity. A low level of expression of hPirh2 was found both at transcriptional and translational level in human hepatocellular carcinoma (HCC) when compared to non-cancerous tissue. Statistical analysis showed that the low expression is associated with lack of differentiation of HCC. In direct binding studies hPirh2b bound p53 indicating that RING-H2 domain is not needed for this interaction.
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PMID:A novel hPirh2 splicing variant without ubiquitin protein ligase activity interacts with p53 and is down-regulated in hepatocellular carcinoma. 2045 52

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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PMID:Role of Pirh2 in mediating the regulation of p53 and c-Myc. 2212 90

Hepatocellular carcinoma (HCC) is one of the most common malignancies in the world, especially in China. Recent researches have shown that E3 ubiquitin ligases Pirh2 (p53-induced RING-H2 protein) is highly expressed in HCC cell lines and is correlated with poor survival and prognostic in patients with HCC; however, the function of Pirh2 in the genesis and the development of HCC remains unclear. Pirh2, a member of the RING finger family, can target p53 for degradation and thereby repress a diverse group of biological activities and involved in many signalling pathways related to the genesis and evolution of cancer. Up to now, four Pirh2 variants had been reported and named Pirh2A, Pirh2B, Pirh2C and Pirh2D. Here we report the existence of two additional isoforms from human hepatocellular liver carcinoma cell line (HepG2 cell) and named as Pirh2E and Pirh2F. Compared to full-length Pirh2A, Pirh2E lacks amino acids 235-261, while Pirh2F is missing C-terminal amino acids 227-261 and both isoforms harbor the RING domain; therefore, we speculate that ubiquitin ligase activity maybe reversed by them. Further studies are required to determine whether Pirh2E and Pirh2F functions in a manner similar to Pirh2A.
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PMID:Identification of Pirh2E and Pirh2F, two additional novel isoforms of Pirh2 ubiquitin ligase from human hepatocellular liver carcinoma cell line. 2276 6

The androgen receptor (AR) for the male hormone androgen plays an important role in regulation of cell survival or death depending on the nature of cellular context and extracellular stimuli. The pro-survival function of AR is mediated mainly by transcriptional regulation of its target genes. By contrast, the pro-death function of AR can be transcription-dependent or -independent, although the underlying mechanism of the latter is incompletely understood. Here we report that, in androgen-independent prostate cancer cells, AR promotes UV-induced apoptosis through down-regulation of basal expression of p21 independently of its transcriptional activity. Down-regulation of basal p21 expression depends on AR N-terminal interacting protein PIRH2, an E3 ligase for proteasomal degradation of p53. Silencing of PIRH2 up-regulates p53, which in turn activates p21 transcription. Consistent with this, knockdown of PIRH2 suppresses UV-induced AR-dependent apoptosis. Our data suggest that AR primes androgen-independent prostate cancer cells to DNA damage-induced apoptosis through the PIRH2-p53-p21 axis.
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PMID:Androgen receptor primes prostate cancer cells to apoptosis through down-regulation of basal p21 expression. 2315 36

The serine threonine kinase checkpoint kinase 2 (CHK2) is a DNA damage checkpoint protein important for the ATM-p53 signaling pathway. In addition to its phosphorylation, CHK2 is also ubiquitylated, and both post-translational modifications are important for its function. However, although the mechanisms that regulate CHK2 phosphorylation are well established, those that control its ubiquitylation are not fully understood. In this study, we demonstrate that the ubiquitin E3 ligase PIRH2 (p53-induced protein with a RING (Really Interesting New Gene)-H2 domain) interacts with CHK2 and mediates its polyubiquitylation and proteasomal degradation. We show that the deubiquitylating enzyme USP28 forms a complex with PIRH2 and CHK2 and antagonizes PIRH2-mediated polyubiquitylation and proteasomal degradation of CHK2. We also provide evidence that CHK2 ubiquitylation by PIRH2 is dependent on its phosphorylation status. Cells deficient in Pirh2 displayed accumulation of Chk2 and enhanced hyperactivation of G1/S and G2/M cell-cycle checkpoints. This hyperactivation was, however, no longer observed in Pirh2-/-Chk2-/- cells, providing evidence for the importance of Chk2 regulation by Pirh2. These findings indicate that PIRH2 has central roles in the ubiquitylation of Chk2 and its turnover and in the regulation of its function.
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PMID:The E3 ligase PIRH2 polyubiquitylates CHK2 and regulates its turnover. 2344 89


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