title: The p53 tumor suppressor is stabilized by inhibitor of growth 1 (ING1) by blocking polyubiquitination.
abstract: The INhibitor of Growth tumor suppressors (ING1-ING5) affect aging, apoptosis, DNA repair and tumorigenesis. Plant homeodomains (PHD) of ING proteins bind histones in a methylation-sensitive manner to regulate chromatin structure. ING1 and ING2 contain a polybasic region (PBR) adjacent to their PHDs that binds stress-inducible phosphatidylinositol monophosphate (PtIn-MP) signaling lipids to activate these INGs. ING1 induces apoptosis independently of p53 but other studies suggest proapoptotic interdependence of ING1 and p53 leaving their functional relationship unclear. Here we identify a novel ubiquitin-binding domain (UBD) that overlaps with the PBR of ING1 and shows similarity to previously described UBDs involved in DNA damage responses. The ING1 UBD binds ubiquitin with high affinity (K(d)∼100 nM) and ubiquitin competes with PtIn-MPs for ING1 binding. ING1 expression stabilized wild-type, but not mutant p53 in an MDM2-independent manner and knockdown of endogenous ING1 depressed p53 levels in a transcription-independent manner. ING1 stabilized unmodified and six multimonoubiquitinated forms of wild-type p53 that were also seen upon DNA damage, but not p53 mutants lacking the six known sites of ubiquitination. We also find that ING1 physically interacts with herpesvirus-associated ubiquitin-specific protease (HAUSP), a p53 and MDM2 deubiquitinase (DUB), and knockdown of HAUSP blocks the ability of ING1 to stabilize p53. These data link lipid stress signaling to ubiquitin-mediated proteasomal degradation through the PBR/UBD of ING1 and further indicate that ING1 stabilizes p53 by inhibiting polyubiquitination of multimonoubiquitinated forms via interaction with and colocalization of the HAUSP-deubiquitinase with p53.
authors: Departments of Biochemistry and Molecular Biology and Oncology, University of Calgary, Calgary, Alberta, Canada.
authors: Subhash
authors: S
authors: Thalappilly
authors: Xiaolan
authors: X
authors: Feng
authors: Svitlana
authors: S
authors: Pastyryeva
authors: Keiko
authors: K
authors: Suzuki
authors: Daniel
authors: D
authors: Muruve
authors: Daniel
authors: D
authors: Larocque
authors: Stephane
authors: S
authors: Richard
authors: Matthias
authors: M
authors: Truss
authors: Andreas
authors: A
authors: von Deimling
authors: Karl
authors: K
authors: Riabowol
authors: Gesche
authors: G
authors: Tallen
mesh_terms: D045744:Cell Line, Tumor; D006801:Humans; D000076023:Inhibitor of Growth Protein 1; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000378:metabolism*; D008954:Models, Biological; D050505:Mutant Proteins / Q000378:metabolism; D009687:Nuclear Proteins / Q000737:chemistry / Q000378:metabolism*; D010743:Phospholipids / Q000378:metabolism; D025821:Polyubiquitin / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D055550:Protein Stability; D017434:Protein Structure, Tertiary; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000378:metabolism*; D043222:Ubiquitin Thiolesterase / Q000378:metabolism; D000076084:Ubiquitin-Specific Peptidase 7; D054875:Ubiquitination
chemical_list: C501503:ING1 protein, human; D000076023:Inhibitor of Growth Protein 1; D047908:Intracellular Signaling Peptides and Proteins; D050505:Mutant Proteins; D009687:Nuclear Proteins; D010743:Phospholipids; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D025821:Polyubiquitin; C464569:USP7 protein, human; D043222:Ubiquitin Thiolesterase; D000076084:Ubiquitin-Specific Peptidase 7; D046988:Proteasome Endopeptidase Complex