Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P05412 (c-Jun)
 11,453 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Homeodomain-interacting protein kinase 2 (HIPK2) is a serine/threonine kinase involved in transcriptional regulation and apoptosis. Here we demonstrate that HIPK2 regulates transforming growth factor (TGF) beta-induced c-Jun NH(2)-terminal kinase (JNK) activation and apoptosis. HIPK2 colocalizes with Daxx, a protein acting in TGF-beta-induced JNK activation and apoptosis, in promyelocytic leukemia (PML) nuclear bodies, and triggers PML-nuclear body disruption and release of Daxx. HIPK2 interacts in vitro and in vivo via its kinase domain with Daxx, and a fraction of Daxx coprecipitates with HIPK2 under physiological conditions. Moreover, overexpression of HIPK2 leads to Daxx phosphorylation, and ectopic expression of HIPK2 activates the JNK signaling pathway, which is enhanced by coexpression of Daxx. HIPK2 signals to JNK via a pathway using Daxx and the mitogen-activated protein kinase kinases MKK4/SEK1 and MKK7. Ectopic expression of HIPK2 and Daxx potentiates TGF-beta-induced apoptosis in human p53-deficient hepatocellular carcinoma cells. Finally, we demonstrate that knockdown of endogenous HIPK2 using RNA interference inhibits TGF-beta-induced JNK activation and apoptosis. Taken together, our findings indicate that HIPK2 participates in the TGF-beta signaling pathway leading to JNK activation and apoptosis.
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PMID:HIPK2 regulates transforming growth factor-beta-induced c-Jun NH(2)-terminal kinase activation and apoptosis in human hepatoma cells. 1467 85

Homeodomain-interacting protein kinase 2 (HIPK2) is involved in transcriptional regulation, growth suppression, and apoptosis. Previous reports showed that HIPK2 can signal cell death via p53, and independently of p53 by activating the c-Jun NH2-terminal kinase (JNK) pathway or mediating CtBP degradation. Here we demonstrate that human HIPK2 is small ubiquitin-related modifier-1 (SUMO-1)-modified in vitro and in vivo at lysine residue 25, a SUMO consensus modification motif conserved in human and mouse HIPK family proteins. SUMO modification of HIPK2 altered neither its nuclear body localization nor its recruitment to promyelocytic leukemia-nuclear bodies. However, SUMO-1 modification inhibited HIPK2-induced JNK activation and p53-independent antiproliferative function. HIPK2 with a mutated SUMO acceptor lysine residue was refractory to inhibition of HIPK2-mediated JNK activation by SUMO-1. Furthermore, we demonstrate that SUMO protease SuPr-1 interacts with HIPK2, and both proteins predominantly colocalize in promyelocytic leukemia-nuclear bodies. SuPr-1 deconjugates SUMO-1 from HIPK2 in vitro and in vivo, which results in modestly increased HIPK2-induced JNK activity. Thus, our data demonstrate that HIPK2 effector function on JNK is modulated through dynamic SUMO-1 modification.
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PMID:Regulation of homeodomain-interacting protein kinase 2 (HIPK2) effector function through dynamic small ubiquitin-related modifier-1 (SUMO-1) modification. 1595 89

Genetic knock out of the transcriptional co-repressor carboxyl-terminal-binding protein (CtBP) in mouse embryonic fibroblasts results in up-regulation of several genes involved in apoptosis. We predicted, therefore, that a propensity toward apoptosis might be regulated through changes in cellular CtBP levels. Previously, we have identified the homeodomain-interacting protein kinase 2 as such a regulator and demonstrated that HIPK2 activation causes Ser-422 phosphorylation and degradation of CtBP. In this study, we found that c-Jun NH2-terminal kinase 1 activation triggered CtBP phosphorylation on Ser-422 and subsequent degradation, inducing p53-independent apoptosis in human lung cancer cells. JNK1 has previously been linked to UV-directed apoptosis. Expression of MKK7-JNK1 or exposure to UV irradiation reduced cellular levels of CtBP via a proteasome-mediated pathway. This effect was prevented by JNK1 deficiency. In addition, sustained activation of the JNK1 pathway by cisplatin similarly triggered CtBP degradation. These findings provide a novel target for chemotherapy in cancers lacking p53.
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PMID:c-Jun NH2-terminal kinase promotes apoptosis by down-regulating the transcriptional co-repressor CtBP. 1698 92

Tumor cell tolerance to nutrient deprivation can be an important factor for tumor progression, and may depend on deregulation of both oncogenes and oncosuppressor proteins. Homeodomain-interacting protein kinase 2 (HIPK2) is an oncosuppressor that, following its activation by several cellular stress, induces cancer cell death via p53-dependent or -independent pathways. Here, we used genetically matched human RKO colon cancer cells harboring wt-HIPK2 (HIPK2(+/+)) or stable HIPK2 siRNA interference (siHIPK2) to investigate in vitro whether HIPK2 influenced cell death in glucose restriction. We found that glucose starvation induced cell death, mainly due to c-Jun NH2-terminal kinase activation, in HIPK2(+/+)cells compared with siHIPK2 cells that did not die. (1)H-nuclear magnetic resonance quantitative metabolic analyses showed a marked glycolytic activation in siHIPK2 cells. However, treatment with glycolysis inhibitor 2-deoxy-D-glucose induced cell death only in HIPK2(+/+) cells but not in siHIPK2 cells. Similarly, siGlut-1 interference did not re-establish siHIPK2 cell death under glucose restriction, whereas marked cell death was reached only after zinc supplementation, a condition known to reactivate misfolded p53 and inhibit the pseudohypoxic phenotype in this setting. Further siHIPK2 cell death was reached with zinc in combination with autophagy inhibitor. We propose that the metabolic changes acquired by cells after HIPK2 silencing may contribute to induce resistance to cell death in glucose restriction condition, and therefore be directly relevant for tumor progression. Moreover, elimination of such a tolerance might serve as a new strategy for cancer therapy.
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PMID:Glucose restriction induces cell death in parental but not in homeodomain-interacting protein kinase 2-depleted RKO colon cancer cells: molecular mechanisms and implications for tumor therapy. 2370 84