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)

The JNK group (for c-Jun N-terminal kinase) of mitogen-activated protein kinases (MAP kinases) is activated in cells in response to environmental stress and cytokines. Activation of JNK is the result of dual phosphorylation by specific upstream kinases which phosphorylate the TxY motif. Much less is known concerning the down-regulation by protein phosphatases. Here, we demonstrate that the tyrosine-specific and constitutively-expressed phosphatase VHR (for VH1-Related) down-regulates the JNK signaling pathway at the level of JNK dephosphorylation. VHR was shown to efficiently dephosphorylate JNK and to form a tight complex with activated JNK when the catalytically-inactive C124S VHR mutant was employed as an in vivo substrate trap. Utilizing an in vitro assay, the transcription factor c-Jun specifically inhibited the ability of VHR to dephosphorylate JNK, likely by sterically blocking access to the phosphorylation sites when JNK and c-Jun form a complex. c-Jun has no effect on the ability of VHR to inactivate the ERK MAP kinases or to hydrolyze artificial substrates. The c-Jun inhibition results are discussed in terms of the resistant-nature of JNK dephosphorylation in cellular extracts and in terms of a general model in which VHR may be a general MAP kinase phosphatase whose specificity and activity are dictated by the presence of MAP kinase-associated proteins that inhibit dephosphorylation.
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PMID:Dual-specificity protein tyrosine phosphatase VHR down-regulates c-Jun N-terminal kinase (JNK). 1197 Nov 92

Cyclin D1 plays an important role in cell cycle progression. In breast cancer, Cyclin D1 expression is deregulated by several mechanisms. We previously showed that in breast cancer cells, overexpression of BRCA1-IRIS induces Cyclin D1 overexpression and increases cell proliferation. BRCA1-IRIS alone or in complex with steroid receptor co-activators was targeted to the cyclin D1 promoter pre-bound by the c-Jun/AP1 and activated its transcription, which could explain the co-overexpression of BRCA1-IRIS and Cyclin D1 in breast cancer cells coupled with their increased proliferation. We report here an alternate or a complementary pathway by which BRCA1-IRIS activates Cyclin D1 expression. BRCA1-IRIS overexpression decreases the expression of the dual specificity phosphatase, DUSP3/VHR, an endogenous inhibitor of several MAPKs, including c-Jun N-terminal kinase. Although, the mechanism by which BRCA1-IRIS overexpression accomplishes that is not yet known, it is sufficient to induce Cyclin D1 overexpression in a human mammary epithelial cell model. Cyclin D1 overexpression could be blocked by co-overexpression of VHR in those cells. Furthermore, in 2 breast cancer cell lines that overexpress both BRCA1-IRIS and Cyclin D1 (MCF-7 and SKBR3) depletion of BRCA1-IRIS by RNA interference attenuated the expression of Cyclin D1 by elevating the expression level of VHR. These data demonstrate a critical role for BRCA1-IRIS in human breast cancer cell-cycle control and suggest that deregulated expression of BRCA1-IRIS is likely to reduce dependence on normal physiological growth stimuli, thereby providing a growth advantage to tumor cells and a potential mechanism of resistance to endocrine therapy.
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PMID:BRCA1-IRIS activates cyclin D1 expression in breast cancer cells by downregulating the JNK phosphatase DUSP3/VHR. 1727 98

Mitogen-activated protein kinase phosphatase 1 (MKP-1) is a tyrosine phosphatase superfamily member that dephosphorylates and inactivates cardinal mitogen-activated protein kinase (MAPK) substrates, such as p38, c-Jun NH(2)-terminal kinase, and extracellular signal-regulated kinase. Although these MAPK substrates regulate many essential cellular processes associated with human diseases, few pharmacological inhibitors have been described. The lack of readily available selective MKP-1 inhibitors has severely limited interrogation of its biological role and was one rationale for using a recently described tricyclic pyrrole-2-carboxamide library in our screening efforts. In this report we demonstrate the pharmacological richness of the pyrrole carboxamide library by the finding that 10 of 172 members inhibited human MKP-1. Two of the pyrrole carboxamides, PSI2106 and MDF2085, were especially notable in vitro inhibitors of recombinant human MKP-1 enzyme activity with IC(50) values of 8.0 +/- 0.9 and 8.3 +/- 0.8 microM, respectively. Both showed some selectivity for MKP-1 over the closely related phosphatases MKP-3, Cdc25B, VHR, and PTP1B. Computational examination of the surface properties near the catalytic site revealed that the phosphatases studied differ significantly in their electrostatic potential at the substrate binding site. The compounds inhibited MKP-1 reversibly but displayed mixed kinetics. Phosphatase inhibition was retained in the presence of physiologically relevant concentrations of glutathione. Molecular docking studies suggested that PSI2106 may interact with His(229) and Phe(299) on MKP-1. These results reveal the power of using a small focused library for identifying pharmacological probes.
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PMID:Structurally unique inhibitors of human mitogen-activated protein kinase phosphatase-1 identified in a pyrrole carboxamide library. 1753 6

Androgen ablation during the initial stages of prostate cancer causes regression of the tumor due to an increase in apoptosis and reduced cellular proliferation. However, prostate cancer invariably progresses to an androgen-independent state for poorly understood reasons. Previous studies showed that c-Jun NH(2) terminal kinase (JNK) is required for 12-O-tetradecanoylphorbol-13-acetate (TPA)- and thapsigargin (TG)-induced apoptosis in the androgen-responsive prostate cancer cell line LNCaP. Androgens protect LNCaP cells from TPA-induced or TG-induced apoptosis via down-regulation of JNK activation. However, the molecular mechanisms of this inhibition are not clear. Here, we systematically investigated the possible regulation of mitogen-activated protein kinase phosphatases/dual-specificity phosphatases during apoptosis of LNCaP cells and found that Vaccinia H1-related protein (VHR/DUSP3) is up-regulated by androgens during inhibition of apoptosis in LNCaP cells, but not in androgen-independent DU145 cells. Ectopic expression of wild-type VHR, but not a catalytically inactive mutant, interfered with TPA- and TG-induced apoptosis. Consistently, small interfering RNA-mediated knockdown of endogenous VHR increased apoptosis in response to TPA or TG in the presence of androgens. Furthermore, COS7 cells stably expressing wild-type VHR, but not a mutant, had a decrease in JNK phosphorylation. In vivo, VHR expression decreased in the androgen-dependent human prostate cancer xenograft CWR22 upon androgen withdrawal and was inversely correlated to JNK phosphorylation. Expression analysis in human prostate cancer specimens showed that VHR is increased in prostate cancer compared with normal prostate. These data show that VHR has a direct role in the inhibition of JNK-dependent apoptosis in LNCaP cells and may therefore have a role in prostate cancer progression.
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PMID:The mitogen-activated protein kinase phosphatase vaccinia H1-related protein inhibits apoptosis in prostate cancer cells and is overexpressed in prostate cancer. 1901 Aug 98

DUSP3 (or Vaccinia virus phosphatase VH1-related; VHR) is a small dual-specificity phosphatase known to dephosphorylate c-Jun N-terminal kinases and extracellular signal-regulated kinases. In human cervical cancer cells, DUSP3 is overexpressed, localizes preferentially to the nucleus, and plays a key role in cellular proliferation and senescence triggering. Other DUSP3 functions are still unknown, as illustrated by recent and unpublished results from our group showing that this enzyme mediates DNA damage response or repair processes. In this study, we sought to identify new interactions between DUSP3 and proteins directly or indirectly involved in or correlated with its biological roles in HeLa cells exposed to gamma or UV radiation. By using GST-DUSP as bait, we pulled down interacting proteins and identified them by LC-MS/MS. Of the 46 proteins obtained, six hits were extensively validated by immune techniques; the proteins Nucleophosmin, HnRNP C1/C2, and Nucleolin were the most promising targets found to directly interact with DUSP3. We then analyzed the DUSP3 interactomes using physical protein-protein interaction networks using our hits as the seed list. The validated hits as well as unvalidated hits fluctuated on the DUSP3 interactomes of HeLa cells, independent of the time post radiation, which confirmed our proteomic and experimental data and clearly showed the proximity of DUSP3 to proteins involved in processes intimately related to DNA repair and senescence, such as Ku70 and Tert, via interactions with nucleolar proteins, which were identified in this study, that regulate DNA/RNA structure and functions.
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PMID:Proteomic, cellular, and network analyses reveal new DUSP3 interactions with nucleolar proteins in HeLa cells. 2424 51