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)

We report here that the fusion of PML, a nuclear protein defined by the t(15;17) chromosomal translocation in acute promyelocytic leukemia, with retinoic acid receptor alpha (RAR alpha) changes the RAR alpha from a retinoic acid (RA)-dependent inhibitor to a RA-dependent activator of AP-1 transcriptional activity. The PML-RAR alpha chimera cooperates with c-Jun and, strikingly, with c-Fos to stimulate the transcription of both synthetic and natural reporter genes containing an AP-1 site. Stimulation is dependent on the concentration of RA and its dose-response curve is comparable to that for activation by RAR alpha of transcription on RA-responsive genes. Further, in the absence of RA, a circumstance in which RAR alpha has no effect on AP-1 activity, PML-RAR alpha is an inhibitor. Deletion of the dimerization, transactivation, or DNA-binding domains of c-Jun and removal of the PML dimerization domain in the PML-RAR alpha hybrid abrogates their transcriptional cooperatively. In view of the association between AP-1 activity and hemopoietic differentiation, we suggest that these properties of PML-RAR alpha could contribute to the leukemic phenotype and its response to RA.
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PMID:The PML-retinoic acid receptor alpha translocation converts the receptor from an inhibitor to a retinoic acid-dependent activator of transcription factor AP-1. 841 4

JEM-1 is a novel gene whose mRNA expression in acute promyelocytic leukemia (APL) is induced by retinoid treatments. The gene product, a 45 kDa basic nuclear factor containing a leucine repeat, was transiently expressed in HeLa or COS-7 cells and immunocharacterized within the nuclei in fine punctuated structures which increase in size after cell transfection. Jem-1 was not expressed in the nucleoli. Experimental deletion of peptide domains of Jem-1 (JemDelta331-400 and Jem DeltaL179-206) showed that its C-terminal sequence (Thr331 --> Leu400) is required for nuclear translocation, while the leucine repeat domain (Arg179 --> Glu206) has no influence on subcellular localization. The Jem-1 protein was not detected in the PML-containing nuclear bodies or in speckled structures containing the splicing factor SC-35. In contrast it was localized in the nucleus in structures containing activator protein-1 (AP-1). DNA mobility shift assays showed that the in vitro translated Jem protein interacts neither with the DNA binding site of AP-1, nor directly with in vitro co-translated c-Fos or/and c-Jun proteins bound to this specific sequence. Interestingly, Jem-1-1 increased substantially the transcriptional activity of c-Jun (three-fold) and more strongly that of ectopically co-expressed c-Fos and c-Jun (five- to six-fold), as measured by a CAT reporter gene driven by a heterologous promoter containing the AP-1 binding site of the human collagenase gene. These synergistic effects were strongly Jem-1 dose-dependent. However, Jem-1 alone showed no activity on the collagenase promoter. A deletion of the leucine repeat of Jem-1 (Arg179 --> Glu206) did not diminish the enhancer capacity of Jem-1 on AP-1 activity. In contrast, the enhanced AP-1 activity was abrogated when Jem-1 was deleted of its C-terminus (Thr331 --> Leu400). We conclude that the 45 kDa nuclear product of the JEM-1 gene has features of a novel transcription cofactor, which is enhancing AP-1 activity without directly interacting with c-Jun or c-Fos proteins. Possible implications of these findings for APL cell maturation are discussed.
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PMID:JEM-1, a novel nuclear co-factor: localisation and functional interaction with AP-1. 1060 19

During a screen to identify c-Jun activators, we isolated a cysteine protease, SuPr-1, that induced c-Jun-dependent transcription independently of c-Jun phosphorylation. SuPr-1 is a member of a new family of proteases that hydrolyze the ubiquitin-like modifier, SUMO-1. SuPr-1 hydrolyzed SUMO-1-modified forms of the promyelocytic leukemia gene product, PML, and altered the subcellular distribution of PML in nuclear PODs (PML oncogenic domains). SuPr-1 also altered the distribution of other nuclear POD-associated proteins, such as CBP and Daxx, that act as transcriptional regulators. SuPr-1 action on transcription was enhanced by PML, and SuPr-1 failed to activate transcription in PML-deficient fibroblasts. Our studies establish an important role for SUMO proteases in transcription.
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PMID:SUMO-1 protease-1 regulates gene transcription through PML. 1241 28

Inorganic arsenic trioxide (As(2)O(3)) is a highly effective treatment for acute promyelocytic leukemia (APL). However, other cancers do not respond well to this form of arsenic at clinically achievable doses. We tested a novel arsenical, S-dimethylarsino-glutathione (darinaparsin) for efficacy in various malignancies in vitro. Darinaparsin is significantly more potent than As(2)O(3) at mediating apoptosis in various malignant cell lines and is highly active against APL cells derived for As(2)O(3) resistance. We provide evidence that darinaparsin triggers apoptosis by inducing signaling pathways that do not completely overlap with As(2)O(3). We show that darinaparsin induces apoptosis and oxidative stress to a greater extent than As(2)O(3), although like As(2)O(3), darinaparsin-induced toxicity is c-Jun NH(2)-terminal kinase-dependent. However, darinaparsin does not induce promyelocytic leukemia/retinoic acid receptor alpha (PML/RAR alpha) degradation or rearrange PML nuclear bodies in APL cells, nor is its toxicity increased by glutathione depletion. Darinaparsin treatment results in higher intracellular arsenic accumulation when compared to As(2)O(3) treatment. This may be explained by our finding that As(2)O(3), but not darinaparsin, is efficiently exported by ABCC1, suggesting increased therapeutic efficacy of darinaparsin in ABCC1-overexpressing tumors. Our studies indicate that darinaparsin efficiently kills tumor cells with increased antioxidant capacity and drug exporters and suggest that darinaparsin may have a broader therapeutic spectrum than As(2)O(3).
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PMID:A novel arsenical has antitumor activity toward As2O3-resistant and MRP1/ABCC1-overexpressing cell lines. 1863 30

Daxx is essential for embryonic development and implicated in apoptosis and transcriptional regulation. It is found only in the animal kingdom and appears to arise first in insects. In the Drosophila genus, the Daxx orthologs are much larger than those in other species. Here we show that in addition to a conserved core of approximately 200 residues, Daxx possesses several conserved domains and two essentially invariable short SUMO-interacting motifs (SIMs), each located at one or the other terminus of the protein. Both can independently interact with SUMO. The Daxx I7/733K double mutant with one mutation in each of the two SIMs no longer interacts with SUMO. Daxx interacts with Ubc9 and this interaction strictly requires at least one SIM. Interestingly, the Ubc9 H20D mutation that abolishes non-covalent Ubc9-SUMO interaction also interrupts Daxx-Ubc9 interaction. Thus, SUMO serves as the intermediate for Daxx-Ubc9 interaction. Surprisingly, Daxx I7/733K double mutant could still colocalize with PML. Furthermore, wt Daxx also strongly colocalizes with PMLDeltaS mutant, in which all three sumoylation sites are mutated, whereas PMLDeltaS only weakly colocalizes with Daxx I7/733K mutant, suggesting that SIM-SUMO interaction is not essential for but enhances PML-Daxx interaction. Remarkably, Daxx strongly stimulates c-Jun-mediated transcription and both SIMs are required for this stimulation. PML also activates c-Jun, which requires all three sumoylation sites. Coexpression of Daxx and PML revealed that they independently regulate c-Jun, with Daxx exerting a dominant role. These results suggest that the conserved SIMs are involved in mediating protein-protein interactions that underlie Daxx's diverse cellular functions.
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PMID:Identification of two independent SUMO-interacting motifs in Daxx: evolutionary conservation from Drosophila to humans and their biochemical functions. 1910 12