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tisdag 3 juli 2018

USP 4 (3p21.31) UNP, UNPh

USP4
USP4 (3p21.31) UNP, Unph

USP4 geeni koodaa proteaasia, joka deubikitinoi useita  kohdeproteiineja, esim ADORA2A ja TRIM21. USP4- proteiini sukkuloi tuman ja sytoplasman väliä ja osallistuu endoplasmisen retikulumin operatiivisen tarkkuuden ylläpitämiseen. Siitä on kolme transkriptivarianttia, jotka koodaavat eri isoformeja.

Kommentti: USP4:n deubikitinaatiokohteita
ADORA2A , adenosine 2A receptor (22q11.23)
TRIM24 (11p15.4), RO52, Ro/SSA,SSA,SSA1) E3 ubiquitin ligase

  • https://www.ncbi.nlm.nih.gov/gene/7375 Also known as UNP; Unph. Summary. The protein encoded by this gene is a protease that deubiquitinates target proteins such as ADORA2A and TRIM21. The encoded protein shuttles between the nucleus and cytoplasm and is involved in maintaining operational fidelity in the endoplasmic reticulum. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2011] Expression. Ubiquitous expression in testis (RPKM 15.1), bone marrow (RPKM 14.6) and 25 other tissues
Lisää USP4:ää koskevia artikkeleita  PuBMed lähteestä löytyy  runsaasti (Related articles in PubMed)
  • USB4 osuutta selvitelty eri syövissä.
  • USP4 prognostisesti edullisena merkkinä eräissä syövissä
    Ubiquitin-specific protease 4 improves the prognosis of the patients in esophageal cancer. Yao R, et al. Cancer Biomark, 2017 Sep 7. PMID 28946564 Taken together, our study uncovered a previously unknown function of USP4 in esophageal cancer and more investigations would be carried out to further study its regulation gene network and molecular biological mechanism in esophageal cancer.
  • USP4 matalia  pitoisuuksia havaittu  pienisoluissa keuhkosyövissä
    The human UNP locus at 3p21.31 encodes two tissue-selective, cytoplasmic isoforms with deubiquitinating activity that have reduced expression in small cell lung carcinoma cell lines. Frederick A, et al. Oncogene, 1998 Jan 15. PMID 9464533 . Cellular fractionation and immunocytochemistry revealed UNP expression localized primarily in the cytoplasm. When we examined a panel of lung-derived cell lines for both UNP mRNA and protein expression, we found reduced levels of UNP protein in all four small cell lung carcinoma cell lines tested. These findings directly contradict and offer alternative interpretations to a number of previously published observations on Unp.
  • USB4 tekee interaktion infterferonisäätelijätekijään IRF8 kanssa  stabiloiden sen K48 deubikitinaatiolla T reg solussa.
    https://www.ncbi.nlm.nih.gov/pubmed/28791349 USP4 interacts and positively regulates IRF8 function via K48-linked deubiquitination in regulatory T cells. Lin R, et al. FEBS Lett, 2017 Jun. PMID 28477415 CD4+ CD25+ regulatory T (Treg) cells comprise a unique subset of T cells required for maintaining immune homeostasis. However, the molecular mechanisms associated with the functional variety of Treg cells are not fully delineated. In the present study, we demonstrate that ubiquitin-specific protease (USP)4 physically interacted with interferon regulatory factor 8 (IRF8) function via a K48-linked deubiquitinase, which stabilized IRF8 protein levels in Treg cells. Depletion of USP4 promoted the polyubiquitination of IRF8 and the upregulation of type 2 inflammatory cytokine gene expression in Treg cells. Consistently, treatment of Treg cells with USP4 inhibitor facilitated the polyubiquitination of IRF8. In addition, the deficiency of USP4 alleviated the suppressive function of Treg cells. Taken together, our results suggest that USP4 interacts with and stabilizes IRF8 to promote the suppressive function of Treg cells
  • USP4 inhiboiva vaikutus rintasyöpään välittyy PDCD4 (programmed cell death 4) - säätelyn kautta.:USP4 säätää ylös PCDC4. Toisaalta: Rintasyövässä on havaittu alentuneita USP4 pitoisuuksia.
    Ubiquitin-specific protease 4 inhibits breast cancer cell growth through the upregulation of PDCD4. Li Y, et al. Int J Mol Med, 2016 Sep. PMID 27430936, Free PMC Article We found that USP4 expression was significantly decreased in breast cancer tissue samples compared with paired normal breast tissue samples (P<0 .001="" a="" as="" identified="" p="" suppressor.="" tumor="" usp4="" was="">
  • USP4 omaa kohdeproteiinin  Wnt- signalointijärjestelmässä: Dishevelled.
    USP4:n K63- deubikitinaatiokohde Dishevelled (Dvl) ja täten USP4 säätää alas kanonisen Wnt/betakateniini-signaloinnin-indusoimaa transkriptionaalista aktiivisuutta.
    These results identify USP4 as a novel regulator of Dvl in Wnt/beta-catenin signal and show its involvement in Wnt3a-induced osteoblast differentiation The canonical Wnt/β-catenin signaling pathway plays a pivotal role and is essentially required for the osteoblast differentiation and bone formation. In this study, we found ubiquitin-specific peptidase 4 (USP4) to strongly inhibit the Wnt/β-catenin signaling by removing Lysine-63 linked poly-ubiquitin chain from Dishevelled (Dvl). Ectopic expression of USP4 promoted β-catenin poly-ubiquitination and thus inhibited Wnt-induced accumulation of cytosolic β-catenin and counteracted Wnt-induced transcriptional activity.
    Moreover, USP4 knockdown or USP4 knockout led to an increase in the active β-catenin levels and in activation of Wnt/β-catenin-induced transcription. Functional studies in C2C12 myoblasts and KS483 osteoprogenitor cells showed that ectopic expression of USP4 resulted in impaired activation of endogenous Wnt3a-induced genes and decreased osteoblast differentiation and mineralization, whereas USP4 depletion showed the opposite effect. These results identify USP4 as a novel regulator of Dvl in Wnt/β-catenin signal and show its involvement in Wnt3a-induced osteoblast differentiation.KEYWORDS: DISHEVELLED; OSTEOBLAST DIFFERENTIATION; UBIQUITINATION; USP4; Wnt3a; β-CATENIN https://en.wikipedia.org/wiki/Wnt_signaling_pathway
  • USP4 deubikitinoi ja stabiloi HDAC2 histonideasetylaasi2:n.
    Histone deacetylases (HDACs) are major epigenetic modulators involved in a broad spectrum of human diseases including cancers. As HDACs are promising targets of cancer therapy, it is important to understand the mechanisms of HDAC regulation. In this study, we show that ubiquitin-specific peptidase 4 (USP4) interacts directly with and deubiquitinates HDAC2, leading to the stabilization of HDAC2. Accumulation of HDAC2 in USP4-overexpression cells leads to compromised p53 acetylation as well as crippled p53 transcriptional activation, accumulation and apoptotic response upon DNA damage. Moreover, USP4 targets HDAC2 to downregulate tumor necrosis factor TNFα-induced nuclear factor (NF)-κB activation. Taken together, our study provides a novel insight into the ubiquitination and stability of HDAC2 and uncovers a previously unknown function of USP4 in cancers.
  • UBS4 toimii partnerina pre- ja post-spliseosomaaliselle proteiinille RNPS1 ja deubikitinoi sen selektiivisesti K63 asemasta mutta ei K48 asemasta.
    RNA-binding protein with serine-rich domain 1 (RNPS1) is a component of pre-splicing and post-splicing multiprotein complexes, which activates constitutive and alternative splicing. RNPS1 participates in the formation of the spliceosome and activates the pre-mRNA splicing process. In the present study, we found that ubiquitin-specific protease 4 (USP4) is a binding partner of RNPS1. Although RNPS1 is polyubiquitinated by both K48- and K63-linkages, USP4 exclusively deubiquitinates K63-linked polyubiquitin chains of RNPS1. We also demonstrate that the catalytic activity of USP4 on ubiquitinated RNPS1 is elevated by squamous cell carcinoma antigen recognized by T cells 3 (Sart3)
  • USP4 toimii myös beta-kateniinispesifisenä deubikitinaasina  Wnt-signaalitiessä.
    USP4 knockdown in HCT116, a colon cancer cell line, reduced invasion and migration activity. β-catenin is a key signal transducer in the canonical WNT pathway and is negatively regulated by ubiquitin-dependent proteolysis. Through screening of various deubiquitinating enzymes (DUBs), we identified ubiquitin specific protease 4 (USP4) as a candidate for β-catenin-specific DUB. The effects of USP4 overexpression or knockdown suggested that USP4 positively controls the stability of β-catenin and enhances β-catenin-regulated transcription. Domain mapping results revealed that the C-terminal catalytic domain is responsible for β-catenin binding and nuclear transport. Examination of colon cancer tissues from patients revealed a correlation between elevated expression levels of USP4 and β-catenin. Consistent with this correlation, USP4 knockdown in HCT116, a colon cancer cell line, reduced invasion and migration activity. These observations indicate that USP4 acts as a positive regulator of the WNT/β-catenin pathway by deubiquitination and facilitates nuclear localization of β-catenin. Therefore, we propose that USP4 is a potential target for anti-cancer therapeutics.
USP4 on avainsäätlijöitä DNA DSB päätyjen trimmauksessa, end resection.
    USP4 cooperates with CtIP in DNA double-strand break end resection. DNA end resection is a highly regulated and criticalstep in DNA double-stranded break (DSB) repair. In higher eukaryotes, DSB resection is initiated by the collaborative action of CtIP and the MRE11-RAD50-NBS1 (MRN) complex. Here, we find that the deubiquitylating enzyme USP4 directly participates in DSB resection and homologous recombination (HR). USP4 confers resistance to DNA damage-inducing agents. Mechanistically, USP4 interacts with CtIP and MRN via a specific, conserved region and the catalytic domain of USP4, respectively, and regulates CtIP recruitment to sites of DNA damage. We also find that USP4 autodeubiquitylation is essential for its HR functions. Collectively, our findings identify USP4 as a key regulator of DNA DSB end resection.
Terminologiasta:  Muutamia  USB4 kohdemolekyylejä

CtIP endonukleaasi, joka trimmaa DNA DSB katkenneitä päätyjä. USP4 tekee interaktion Ct1P:n kanssa  spesifisen konservatiivisen domeenin kautta ja MRN:n kansa katalyyttisen domeenin kautta


Dishevelled (Wnt-signalointijärjestelmän molekyyli) , jonka USB4 deubikitinoi .
DVL; DRS2; DVL1L1; DVL1P1DVL1, the human homolog of the Drosophila dishevelled gene (dsh) encodes a cytoplasmic phosphoprotein that regulates cell proliferation, acting as a transducer molecule for developmental processes, including segmentation and neuroblast specification

HDAC2, histonideasetylaasi, jonka USP4 deubkitinoi.
 https://www.ncbi.nlm.nih.gov/gene/3066 HD2; RPD3; YAF1 Summary
This gene product belongs to the histone deacetylase family. Histone deacetylases act via the formation of large multiprotein complexes, and are responsible for the deacetylation of lysine residues at the N-terminal regions of core histones (H2A, H2B, H3 and H4). This protein forms transcriptional repressor complexes by associating with many different proteins, including YY1, a mammalian zinc-finger transcription factor. Thus, it plays an important role in transcriptional regulation, cell cycle progression and developmental events. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2010]

RNPS1 (16p13.3 ). pre- ja postspliseosomaalinen proteiini, jonka partneri USB4 on.
E5.1 Summary This gene encodes a protein that is part of a post-splicing multiprotein complex involved in both mRNA nuclear export and mRNA surveillance. mRNA surveillance detects exported mRNAs with truncated open reading frames and initiates nonsense-mediated mRNA decay (NMD). When translation ends upstream from the last exon-exon junction, this triggers NMD to degrade mRNAs containing premature stop codons. This protein binds to the mRNA and remains bound after nuclear export, acting as a nucleocytoplasmic shuttling protein. This protein contains many serine residues. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2013]

Spliseosomimekanismin periaate (Hyvä video) . Tästä pitäisi jäädä normaali exoneista koottu hyväksytty mRNA joka lähtee sytosoliin, muu mRNA joutuu hajoitukseen (decay) ja intronijoukon pitäisi hajota (degradation), tuman puolella ja spliceosomin työkalujäsenet käytetään uudestaan. https://www.youtube.com/watch?v=Dp_b9elTxdc

  • PDCD4 , H731 (10q25.2), tuumorisuppressori, jonka USP4 säätää ylös. https://www.ncbi.nlm.nih.gov/gene/27250 This gene is a tumor suppressor and encodes a protein that binds to the eIF4A1 (DDX2A, DEAD box helicase) , eukaryotic translation initiation factor 4A1 and inhibits its function by preventing RNA binding. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2010

”… programmed cell death 4 (PCD4) was identified to be a target of USP4, which plays a role as a tumor suppressor. As a whole, our findings sugggest that USP4 acts as a tumor suppressor in breast cancer and that it may be an effective target for the treatment of breast cancer.

PDCD4 saa ubikitinaationsa CRL3(Cul3)IBTK vaikutuksesta. https://www.ncbi.nlm.nih.gov/pubmed/25882842
Pdcd4:n repressiokohde on Bcl-xL (Bcl2 antiapotoottisen perheen alaperheestä).

Erityispiirteitä eIF4A1:stä (DDX2A, DEAD box helicase, se on esim antiviraali Dengueta vastaan).


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