HAUSP, a novel deubiquitinase for Rb – MDM2 the critical regulator. (10th June 2014)

• Record Type: Journal Article
• Authors: Bhattacharya, Seemana; Ghosh, Mrinal K.
• Is Part Of: FEBS journal. Volume 281:Number 13(2014)
• Page Start: 3061
• Page End: 3078
• Publication Date: 2014-06-10
• Subjects: Biochemistry -- Periodicals; Molecular biology -- Periodicals; Pathology, Molecular -- Periodicals; 572
• DOI: 10.1111/febs.12843
• Languages: English
• ISSNs: 1742-464X

Abstract

<abstract abstract-type="main" id="febs12843-abs-0001"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="febs12843-sec-0001" sec-type="section"> <p>Tumor suppressor retinoblastoma‐associated protein (Rb) is an important cell cycle regulator, arresting cells in early G1. It is commonly inactivated in cancers and its level is maintained during the cell cycle. Rb is regulated by various post‐translational modifications such as phosphorylation, acetylation, ubiquitination and so on. Several E3 ligases including murine double minute 2 (MDM2) promote the degradation of Rb. This study focuses on the role of HAUSP (herpes virus associated ubiquitin specific protease) on Rb. Here, we show that HAUSP colocalizes and interacts with Rb to stabilize it from proteasomal degradation by removing wild‐type and K48‐linked ubiquitin chains in human embryonic kidney 293 (HEK293) cells. HAUSP deubiquitinates Rb <italic>in vivo</italic> and <italic>in vitro</italic>, leading to an increased cell population in the G1 phase. Hence, HAUSP is a novel deubiquitinase for Rb. Immunohistochemistry, western blotting and cell‐based assays show that HAUSP is overexpressed in glioma and contributes towards glioma progression. However, HAUSP activity on Rb is abrogated in glioma (cancer), where these two proteins show an inverse relationship. MDM2 (a known substrate of HAUSP) serves as a better target for HAUSP‐mediated deubiquitination in cancer cells, facilitating degradation of Rb and oncogenic progression. This novel regulatory axis is proteasome mediated, p53 independent, and the level of MDM2 is critical. The shift in equilibrium by differential deubiquitination in regulation of Rb explains a subtle difference existing between normal and cancer cells. This leads to speculation about a new possibility for distinguishing cancer cells from normal cells at the molecular level, which may be investigated for therapeutic intervention in the future.</p> </sec> <sec id="febs12843-sec-0002" sec-type="section"> <title>Structured digital abstract</title> <p> <list id="febs12843-list-0001" list-type="bullet"> <list-item> <p> <ext-link ext-link-type="uri" xlink:href="http://www.uniprot.org/uniprot/Q93009" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink">HAUSP</ext-link> and <ext-link ext-link-type="uri" xlink:href="http://www.uniprot.org/uniprot/P06400" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink">Rb</ext-link> <ext-link ext-link-type="uri" xlink:href="http://www.ebi.ac.uk/ontology-lookup/?termId=MI:0403" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink">colocalize</ext-link> by <ext-link ext-link-type="uri" xlink:href="http://www.ebi.ac.uk/ontology-lookup/?termId=MI:0416" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink">fluorescence microscopy</ext-link> (<ext-link ext-link-type="uri" xlink:href="http://www.ebi.ac.uk/intact/interaction/EBI-9521802" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink">View interaction</ext-link>)</p> </list-item> <list-item> <p> <ext-link ext-link-type="uri" xlink:href="http://www.uniprot.org/uniprot/Q93009" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink">HAUSP</ext-link> <ext-link ext-link-type="uri" xlink:href="http://www.ebi.ac.uk/ontology-lookup/?termId=MI:0407" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink">binds</ext-link> to <ext-link ext-link-type="uri" xlink:href="http://www.uniprot.org/uniprot/P06400" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink">Rb</ext-link> by <ext-link ext-link-type="uri" xlink:href="http://www.ebi.ac.uk/ontology-lookup/?termId=MI:0096" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink">pull down</ext-link> (<ext-link ext-link-type="uri" xlink:href="http://www.ebi.ac.uk/intact/interaction/EBI-9521936" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink">View interaction</ext-link>)</p> </list-item> <list-item> <p> <ext-link ext-link-type="uri" xlink:href="http://www.uniprot.org/uniprot/Q93009" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink">HAUSP</ext-link> <ext-link ext-link-type="uri" xlink:href="http://www.ebi.ac.uk/ontology-lookup/?termId=MI:0915" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink">physically interacts</ext-link> with <ext-link ext-link-type="uri" xlink:href="http://www.uniprot.org/uniprot/P06400" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink">Rb</ext-link> by <ext-link ext-link-type="uri" xlink:href="http://www.ebi.ac.uk/ontology-lookup/?termId=MI:0006" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink">anti bait coip</ext-link> (<ext-link ext-link-type="uri" xlink:href="http://www.ebi.ac.uk/intact/interaction/EBI-9521864" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink">1</ext-link>, <ext-link ext-link-type="uri" xlink:href="http://www.ebi.ac.uk/intact/interaction/EBI-9521845" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink">2</ext-link>, <ext-link ext-link-type="uri" xlink:href="http://www.ebi.ac.uk/intact/interaction/EBI-9521857" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink">3</ext-link>, <ext-link ext-link-type="uri" xlink:href="http://www.ebi.ac.uk/intact/interaction/EBI-9521883" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink">4</ext-link>, <ext-link ext-link-type="uri" xlink:href="http://www.ebi.ac.uk/intact/interaction/EBI-9521831" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink">5</ext-link>, <ext-link ext-link-type="uri" xlink:href="http://www.ebi.ac.uk/intact/interaction/EBI-9521876" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink">6</ext-link>)</p> </list-item> </list> </p> </sec> </abstract>