Repression of the Antiapoptotic Molecule Galectin-3 by Homeodomain-Interacting Protein Kinase 2-Activated p53 Is Required for p53-Induced Apoptosis

Cecchinelli, Barbara; Lavra, Luca; Rinaldo, Cinzia; Iacovelli, Stefano; Gurtner, Aymone; Gasbarri, Alessandra; Ulivieri, Alessandra; Prete, Fabrizio Del; Trovato, Maria; Piaggio, Giulia; Bartolazzi, Armando; Soddu, Silvia; Sciacchitano, Salvatore

doi:10.1128/mcb.00959-05

Cited by 97 publications

(93 citation statements)

References 56 publications

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“…The autoregulatory control loop whereas p53 induces Mdm2 which on the contrary inhibits p53 [5,6] can be interrupted by zinc. The zinc-induced MDM2 downregulation relieves the MDM2-induced HIPK2 degradation [15] and HIPK2 is now available for p53Ser46 phosphorylation [10] and for MDM2 phosphorylation and proteasomal degradation [26].…”

Section: Discussionmentioning

confidence: 99%

“…DNAdamage-induced phosphorylation of its N-terminus contributes to p53 stability by preventing MDM2 from degrading it [5]. Homeodomain-interacting protein kinase-2 (HIPK2) was identified as a p53-interacting protein [6,7] that specifically phosphorylates p53 at Ser46 for transcriptional activation of pro-apoptotic factors such as p53AIP1, PIG3, Bax, Noxa, Puma and KILLER/DR5 [7][8][9], as well as for the repression of the anti-apoptotic factor galectin-3 [10]. Moreover, HIPK2-induced p53Ser46 phosphorylation prevents the MDM2-mediated p53 ubiquitination recovering p53 apoptotic function [11].…”

Section: Introductionmentioning

confidence: 99%

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Counteracting MDM2‐induced HIPK2 downregulation restores HIPK2/p53 apoptotic signaling in cancer cells

Nardinocchi¹,

Puca

D’Orazi

2010

FEBS Letters

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a b s t r a c tHomeodomain-interacting protein kinase-2 (HIPK2) is a crucial regulator of p53 apoptotic function by phosphorylating serine 46 (Ser46) in response to DNA damage. In tumors with wild-type p53, its tumor suppressor function is often impaired by MDM2 overexpression that targets p53 for proteasomal degradation. Likewise, MDM2 targets HIPK2 for protein degradation impairing p53-apoptotic function. Here we report that zinc antagonised MDM2-induced HIPK2 degradation as well as p53 ubiquitination. The zinc inhibitory effect on MDM2 activity leads to HIPK2-induced p53Ser46 phosphorylation and p53 pro-apoptotic transcriptional activity. These results suggest that zinc derivatives are potential molecules to target the MDM2-induced HIPK2/p53 inhibition.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Counteracting MDM2‐induced HIPK2 downregulation restores HIPK2/p53 apoptotic signaling in cancer cells

Nardinocchi¹,

Puca

D’Orazi

2010

FEBS Letters

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“…HIPK2 binds to the C-terminal domain of p53 and specifically phosphorylates p53 at the NH 2 -terminal Ser46 for the p53-mediated transcriptional activation of proapoptotic factors such as p53AIP1, PIG3, Bax, Noxa, Puma and KILLER/DR5 (D 'Orazi et al, 2002;Di Stefano et al, 2004a;Pistritto et al, 2007), as well as for the repression of the antiapoptotic factor galectin-3 (Cecchinelli et al, 2006). Ser46 locates in the TAD 2 (TAD2, residues 43-63) of p53 that is necessary for apoptosis.…”

Section: Hipk2 Phosphorylates P53 At Ser46 and Mediates Apoptosismentioning

confidence: 99%

Regulation of p53 activity by HIPK2: molecular mechanisms and therapeutical implications in human cancer cells

et al. 2010

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The p53 protein is the most studied tumor suppressor and the p53 pathway has been shown to mediate cellular stress responses that are disrupted when cancer develops. After DNA damage, p53 is activated as transcription factor to directly induce the expression of target genes involved in cell-cycle arrest, DNA repair, senescence and, importantly, apoptosis. Post-translational modifications of p53 are essential for the activation of p53 and for selection of target genes. The tumor suppressor homeodomain-interacting protein kinase-2 (HIPK2) is a crucial regulator of p53 apoptotic function by phosphorylating its N-terminal serine 46 (Ser46) and facilitating Lys382 acetylation at the C-terminus. HIPK2 is activated by numerous genotoxic agents and can be deregulated in tumors by several conditions including hypoxia. Recent findings suggest that HIPK2 active/inactive protein can affect p53 function in multiple and unexpected ways. This makes p53 as well as HIPK2 interesting targets for cancer therapy. Hence, understanding the role of HIPK2 as p53 activator may provide important insights in the process of tumor progression, and may also serve as the crucial point in the diagnostic and therapeutical aspects of cancer.

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“…Renal/glomerular FN1, COL4A1, RAGE, NOX4 and GAL-3 protein levels Renal content and distribution of ECM proteins, AGE receptors and NOX4 were assessed by immunohistochemistry, as previously reported [34], using rabbit polyclonal antibodies to human FN1 (Sigma), mouse COL4A1 (Abcam, Cambridge, UK), human RAGE (amino acids 42-59; Abcam), recombinant glutathione S-transferasemouse NOX4 (299-515) [40] and a rat monoclonal antibody against human GAL3 [41]. Sections were analysed using the Optimas 6.5 image analysis system (Optimas; MediaCybernetics, Silver Spring, MD, USA) and results are expressed as percentage of glomerular area positive to each protein.…”

Section: Methodsmentioning

confidence: 99%

Ablation of the gene encoding p66Shc protects mice against AGE-induced glomerulopathy by preventing oxidant-dependent tissue injury and further AGE accumulation

et al. 2007

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Aims/hypothesis AGEs have been implicated in renal disease associated with ageing, diabetes and other age-related disorders. Reactive oxygen species (ROS) promote formation of AGEs, which cause AGE-receptor-mediated ROS generation with activation of signalling pathways leading to tissue injury and further AGE accumulation. ROS generation is regulated by the Src homology 2 domain-containing transforming protein C1 (Shc1) isoform p66 Shc , whose deletion has been shown to protect from tissue injury induced by ageing, diabetes, hyperlipidaemia and ischaemia-reperfusion by preventing oxidative stress. This study was aimed at assessing the role of p66Shc in the modulation of oxidative stress and oxidant-dependent renal injury induced by AGEs. Methods For 10 weeks, male p66 shc knockout (KO) and wild-type (WT) mice were injected with 60 μg/day albumin modified or unmodified by N " À carboxymethyl ð Þ lysine (CML). Mice were then killed for the assessment of renal function and structure, as well as systemic and renal tissue oxidative stress. Results Upon CML injection, KO mice, in contrast to WT mice, showed no or only mild forms of proteinuria, glomerular hypertrophy, mesangial expansion, glomerular sclerosis, renal/glomerular cell apoptosis and extracellular matrix upregulation. Moreover, KO mice had lower circulating and tissue AGEs than WT mice and unchanged plasma isoprostane 8-epi-prostaglandin-F 2! levels, renal/ glomerular CML, 4-hydroxy-2-nonenal, AGE receptor and NAD(P)H oxidase 4 (NOX4) content (and expression of the corresponding genes), and nuclear factor κB activation (NFκB). Mesangial cells from KO mice exposed to CML showed no or slight increase in ROS levels and NFκB activation, again at variance with WT cells. Conclusions/interpretation These data indicate that p66 Shc participates in the pathogenesis of AGE-dependent glomerulopathy by mediating AGE-induced tissue injury and further AGE formation through ROS-dependent mechanisms involving NFκB activation and upregulation of Nox4 expression and NOX4 production.

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Repression of the Antiapoptotic Molecule Galectin-3 by Homeodomain-Interacting Protein Kinase 2-Activated p53 Is Required for p53-Induced Apoptosis

Cited by 97 publications

References 56 publications

Counteracting MDM2‐induced HIPK2 downregulation restores HIPK2/p53 apoptotic signaling in cancer cells

Counteracting MDM2‐induced HIPK2 downregulation restores HIPK2/p53 apoptotic signaling in cancer cells

Regulation of p53 activity by HIPK2: molecular mechanisms and therapeutical implications in human cancer cells

Ablation of the gene encoding p66Shc protects mice against AGE-induced glomerulopathy by preventing oxidant-dependent tissue injury and further AGE accumulation

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