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HIPK2 — TP53

Pathways - manually collected, often from reviews:

• NCI Pathway Database p53 pathway: HIPK2 (HIPK2) → p53 (tetramer) complex (TP53) (modification, activates)
  Hofmann et al., Nat Cell Biol 2002*, D'Orazi et al., Nat Cell Biol 2002*, Mantovani et al., Nature structural & molecular biology 2007*
  Evidence: mutant phenotype, assay, physical interaction

Protein-Protein interactions - manually collected from original source literature:

Studies that report less than 10 interactions are marked with *

• IRef Bind_translation Interaction: TP53 — HIPK2 (unspecified method) Wang et al., BMC molecular biology 2001*
• IRef Bind_translation Interaction: TP53 — HIPK2 (experimental interaction detection) Wang et al., BMC molecular biology 2001*
• IRef Biogrid Interaction: HIPK2 — TP53 (physical association, affinity chromatography technology) Di Stefano et al., FEBS Lett 2005*
• IRef Biogrid Interaction: HIPK2 — TP53 (physical association, affinity chromatography technology) Rinaldo et al., Mol Cell 2007*
• IRef Biogrid Interaction: HIPK2 — TP53 (direct interaction, enzymatic study) Rinaldo et al., Mol Cell 2007*
• IRef Biogrid Interaction: HIPK2 — TP53 (direct interaction, pull down) Hofmann et al., Nat Cell Biol 2002*
• IRef Biogrid Interaction: HIPK2 — TP53 (physical association, affinity chromatography technology) Hofmann et al., Nat Cell Biol 2002*
• IRef Biogrid Interaction: HIPK2 — TP53 (direct interaction, enzymatic study) Hofmann et al., Nat Cell Biol 2002*
• IRef Biogrid Interaction: HIPK2 — TP53 (direct interaction, two hybrid) Kim et al., J Biol Chem 2002*
• IRef Biogrid Interaction: HIPK2 — TP53 (direct interaction, pull down) Sung et al., FEBS Lett 2005*
• IRef Biogrid Interaction: HIPK2 — TP53 (physical association, affinity chromatography technology) Li et al., Oncogene 2011*
• MIPS CORUM DAXX-Axin-p53-HIPK2 complex: DAXX-Axin-p53-HIPK2 complex complex (AXIN1-DAXX-HIPK2-TP53) Li et al., Cancer Res 2007*
• MIPS CORUM Axin-p53-HIPK2 complex: Axin-p53-HIPK2 complex complex (AXIN1-HIPK2-TP53) Rui et al., EMBO J 2004*
• MIPS CORUM FHL2-p53-HIPK2 complex: FHL2-p53-HIPK2 complex complex (FHL2-HIPK2-TP53) Lee et al., Biochem Biophys Res Commun 2006*
• IRef Corum Interaction: Complex of HIPK2-TP53-AXIN1 (association, anti bait coimmunoprecipitation) Rui et al., EMBO J 2004*
• IRef Corum Interaction: Complex of TP53-FHL2-HIPK2 (association, coimmunoprecipitation) Lee et al., Biochem Biophys Res Commun 2006*
• IRef Corum Interaction: Complex of TP53-AXIN1-HIPK2-DAXX (association, anti bait coimmunoprecipitation) Li et al., Cancer Res 2007*
• IRef Hprd Interaction: Complex of TP53-HIPK2-FHL2-TP53-FHL2-HIPK2-HIPK2-TP53-FHL2 (in vivo) Lee et al., Biochem Biophys Res Commun 2006*
• IRef Hprd Interaction: TP53 — HIPK2 (in vitro) D'Orazi et al., Nat Cell Biol 2002*, Saito et al., J Biol Chem 2002*, Kim et al., J Biol Chem 2002*, Sung et al., FEBS Lett 2005*
• IRef Hprd Interaction: TP53 — HIPK2 (in vivo) D'Orazi et al., Nat Cell Biol 2002*, Saito et al., J Biol Chem 2002*, Kim et al., J Biol Chem 2002*, Sung et al., FEBS Lett 2005*
• IRef Intact Interaction: Complex of AXIN1-TP53-AXIN1-HIPK2-HIPK2-TP53 (physical association, anti tag coimmunoprecipitation) Li et al., Oncogene 2011*
• IRef Intact Interaction: TP53 — HIPK2 (direct interaction, pull down) Sung et al., FEBS Lett 2005*
• IRef Intact Interaction: TP53 — HIPK2 (physical association, anti bait coimmunoprecipitation) Di Stefano et al., FEBS Lett 2005*
• MIPS Negatome - no physical interaction between proteins Interaction: HIPK2 — TP53 (Absence of interaction, western blot) Wang et al., BMC molecular biology 2001*
• IRef Ophid Interaction: TP53 — HIPK2 (aggregation, interologs mapping) Brown et al., Bioinformatics 2005

Text-mined interactions from Literome

Wang et al., BMC molecular biology 2001 : HIPK2 overexpression leads to stabilization of p53 protein and increased p53 transcriptional activity by decreasing Mdm2 protein levels ... Overexpression of HIPK2 leads to an increase of p53 protein expression or stability, which becomes enhanced further in the presence of the DNA damaging drug doxorubicin ... The effects of HIPK2 on p53 are not observed with kinase deficient HIPK2 mutants ... However, HIPK2 is not sufficient for phosphorylation of three crucial serine residues of p53, suggesting that HIPK2 induced p53 activation does not involve phosphorylation of p53 ... Instead, HIPK2 leads to a downregulation of p53 induced Mdm2 protein and this may lead to stabilization of p53 ... The data suggest that HIPK2 plays a critical role in p53 mediated cellular responses by removing the p53 inhibitor protein Mdm2 via modification of the protein itself or its intracellular movement
Hofmann et al., Nat Cell Biol 2002 : Regulation of p53 activity by its interaction with homeodomain interacting protein kinase-2 ... Accordingly, the kinase function of HIPK2 mediates the increased expression of p53 target genes, which results in growth arrest and the enhancement of UV-induced apoptosis
Möller et al., Oncogene 2003 : In summary, these experiments reveal a novel function for Sp100 as a coactivator for HIPK2 mediated p53 activation
Di Stefano et al., Oncogene 2004 (Adenocarcinoma...) : Here, we investigated the role of HIPK2 in the activation of p53 in the presence of MDM2
Rui et al., EMBO J 2004 : Axin, but not AxindeltaHIPK2, activates HIPK2 mediated p53 phosphorylation at Ser 46, facilitating p53 dependent transcriptional activity and apoptosis
Di Stefano et al., Oncogene 2005 : Here we show that HIPK2 contributes to p53 regulation, independently from serine 46 phosphorylation upon nonapoptotic DNA damage such as that induced by cytostatic doses of cisplatin
Di Stefano et al., FEBS Lett 2005 : First, in wtp53 carrying cells HIPK2 dependent p53Ser46 phosphorylation selectively inhibits MDM2 at transcriptional level
Lee et al., Biochem Biophys Res Commun 2006 : To understand the molecular mechanism underlying HIPK2 regulation of the transcriptional activation by p53 , we sought to identify the protein that interacts with HIPK2
Gresko et al., EMBO J 2006 : Early induced p53 allows caspase mediated cleavage of HIPK2 following aspartic acids 916 and 977
Cecchinelli et al., Mol Cell Biol 2006 : Previously, it has been reported that phosphorylation of p53 at Ser46 is important for transcription of proapoptotic genes and induction of apoptosis and that homeodomain interacting protein kinase 2 ( HIPK2 ) is specifically involved in these functions
Wesierska-Gadek et al., J Cell Biochem 2007 (Breast Neoplasms) : The overexpression of wild-type but not kinase inactive HIPK2 increased the basal and ROSC induced level of p53 phosphorylation at Ser-46 and strongly enhanced the rate of apoptosis in cells exposed to ROSC
Pierantoni et al., J Clin Invest 2007 (Breast Neoplasms...) : We found that HMGA1 overexpression promoted HIPK2 relocalization in the cytoplasm and inhibition of p53 apoptotic function, while HIPK2 overexpression reestablished HIPK2 nuclear localization and sensitivity to apoptosis ... HIPK2 depletion by RNA interference suppressed the antiapoptotic effect of HMGA1, which indicates that HIPK2 is the target required for HMGA1 to repress the apoptotic activity of p53
Dauth et al., Cancer Res 2007 : Down-regulation of HIPK2 by RNA interference specifically inhibits IR-induced phosphorylation of p53 at Ser ( 46 )
Rinaldo et al., Mol Cell 2007 : Here, we show that p53 represses its proapoptotic activator HIPK2 via MDM2 mediated degradation, whereas a degradation-resistant HIPK2 mutant has increased apoptotic activity
Puca et al., Cancer Res 2008 (Colonic Neoplasms) : These results show a critical role of HIPK2 in maintaining the transactivation activity of wtp53 and further suggest that low expression of HIPK2 may impair the p53 function in tumors harboring wtp53
Raina et al., Cancer Biol Ther 2008 (Colorectal Neoplasms...) : HIPK2 mediated phosphorylation of p53 on Ser-46 was further associated with a shift from expression of the cell cycle arrest related p21 gene to the apoptosis related PUMA gene
Nardinocchi et al., PloS one 2009 : Zinc supplementation to hypoxia treated cells increased HIPK2 protein stability and nuclear accumulation, leading to restoration of HIPK2 binding to HIF-1alpha promoter, repression of MDR1, Bcl2, and VEGF genes, and activation of the p53 apoptotic response to drug ... We show here for the first time that hypoxia induced HIPK2 deregulation was counteracted by zinc that restored HIPK2 suppression of HIF-1 pathway and reactivated p53 apoptotic response to drug, underscoring the potential use of zinc supplementation in combination with chemotherapy to address hypoxia and improve tumor treatment
Wesierska-Gadek et al., Acta biochimica Polonica 2009 (Breast Neoplasms...) : HIPK2 mediated activation of the p53 transcription factor by phosphorylation at Ser46 results in upregulation of p53AIP1 protein
Puca et al., Molecular cancer 2009 : These results reveal a novel role for HIPK2 in activating p53 apoptotic transcription
Petroni et al., Mol Cancer Res 2011 (Neuroblastoma) : The p53 ( S46 ) kinase HIPK2 accumulates on MYCN expression, and its depletion by RNA interference impairs p53 ( S46 ) phosphorylation and apoptosis
Muschik et al., PloS one 2011 : Thus, cutaneous HPV23 E6 prevents HIPK2 mediated p53 Ser 46 phosphorylation, which may favour survival of UV-damaged keratinocytes and skin carcinogenesis by apoptosis evasion
Guerra et al., PloS one 2012 : The HIPKs have been shown to be involved in growth regulation and apoptosis, with numerous studies highlighting HIPK regulation of the tumor suppressor p53
Kumar et al., Oncogenesis 2013 : Tumor suppressor protein Pdcd4 interacts with Daxx and modulates the stability of Daxx and the Hipk2 dependent phosphorylation of p53 at serine 46 ... We show that Pdcd4 also disrupts the Daxx-Hipk2 interaction and inhibits the phosphorylation of p53