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)

Several polyamine analogues have efficacy against a variety of epithelial tumor models including breast cancer. Recently, a novel class of polyamine analogues designated as oligoamines has been developed. Here, we demonstrate that several representative oligoamine compounds inhibit in vitro growth of human breast cancer MDA-MB-435 cells. The activator protein-1 (AP-1) transcriptional factor family members, c-Jun and c-Fos, are up-regulated by oligoamines in MDA-MB-435 cells, suggesting a possible AP-1-dependent induction of apoptosis. However, the use of a novel c-Jun NH(2)-terminal kinase (JNK) inhibitor, SP600125, suggests that inhibition of c-Jun activity sensitized tumor cells to oligoamine-induced cell death. To directly test this hypothesis, cells were stably transfected with the dominant-negative mutant c-Jun (TAM67), which lacks the NH(2)-terminal transactivation domain. Cells overexpressing TAM67 exhibit normal growth kinetics but demonstrate a significantly increased sensitivity to oligoamine cytotoxicity and attenuated colony formation after oligoamine treatment. Furthermore, oligoamine treatment leads to more profound caspase-3 activation and poly(ADP-ribose) polymerase cleavage in TAM67 transfectants, suggesting that c-Jun acts as an antiapoptosis factor in MDA-MB-435 cells in response to oligoamine treatment. These findings indicate that oligoamine-inducible AP-1 plays a prosurvival role in oligoamine-treated MDA-MB-435 cells and that JNK/AP-1 might be a potential target for enhancing the therapeutic efficacy of polyamine analogues in human breast cancer.
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PMID:Regulation of polyamine analogue cytotoxicity by c-Jun in human MDA-MB-435 cancer cells. 1498 64

Cancer progression depends on an accumulation of metastasis-supporting cell signaling molecules, which target signal transduction pathways and, ultimately, gene expression. One such molecule, osteopontin (OPN), represents a key molecular signaling event in tumor progression and metastasis. However, the transcriptional regulatory mechanisms that underlie OPN expression in the setting of breast cancer have not been well studied. In this regard, we have examined the differential transcriptional regulation of OPN in the murine mammary epithelial tumor cell lines, 4T1 and 4T07, which are sublines derived from the parental population of 410.4 cells from Balb/cfC3H mice. These lines are phenotypically heterogeneous in their metastatic behavior. 4T1 hematogenously metastasizes to the lung, liver, bone, and brain, whereas 4T07 is highly tumorigenic but fails to metastasize. The tumor growth and metastatic spread of 4T1 cells closely mimics stage IV breast cancer. We demonstrate that a Ras-independent, phosphoinositide-3 kinase-dependent, c-Jun N-terminal kinase-dependent phosphorylation of c-Jun results in binding of an AP-1 c-Jun homodimer to the OPN promoter in 4T1 cells. This differential up-regulation of OPN gene transcription and protein expression in 4T1 cells conveys in vitro correlates of a metastatic phenotype. These results provide new insight into the transcriptional regulation of OPN as a key mediator of metastatic behavior in malignancy.
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PMID:Differential osteopontin expression in phenotypically distinct subclones of murine breast cancer cells mediates metastatic behavior. 1534 45

Sarcomatoid carcinomas (SC) of the lung are a heterogeneous group of nonsmall cell lung carcinomas (NSCLC) containing a sarcoma or sarcoma-like component. SC may represent an epithelial neoplasm undergoing divergent tissue differentiation originating from a single clone. Epithelial-mesenchymal transition (EMT) best describes the origin of the spindle and giant cells. We aimed to define chromosomal aberrations within the subgroups of SC and if EMT does play a role in SC. Twenty-two SC were investigated by chromosomal comparative genomic hybridization (CGH). Immunohistochemical staining was performed with antibodies for E-cadherin, Vimentin, c-Fos, c-Jun, Snail, TGFbeta1, Notch1, beta-catenin, Glycogen synthase kinase 3beta (GSK3beta), and Fascin. Gains occurred more frequently than losses (70.5 vs 29.5%). The shortest regions of overlap were gains on chromosomes 8q and 7 followed by 1q, 3q, and 19, supporting the common origin of the different subtypes of SC. The immunohistochemical staining suggests that the sarcomatoid components of SC might have undergone EMT, not triggered by the signaling pathways Notch1, Snail, and TGFbeta1, but probably initiated by an upregulation of c-Jun and a consecutive overexpression of Vimentin and Fascin. The Wnt-pathway was not deregulated because combined membrane and cytoplasmic reactivity for beta-catenin and GSK3beta was observed.
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PMID:Sarcomatoid carcinomas of the lung--are these histogenetically heterogeneous tumors? 1694 Nov 52

The transcription factor Sp1 is ubiquitously expressed in different cells and thereby regulates the expression of genes involved in many cellular processes. This study reveals that Sp1 was phosphorylated during the mitotic stage in three epithelial tumor cell lines and one glioma cell line. By using different kinase inhibitors, we found that during mitosis in HeLa cells, the c-Jun NH(2)-terminal kinase (JNK) 1 was activated that was then required for the phosphorylation of Sp1. In addition, blockade of the Sp1 phosphorylation via inhibition JNK1 activity in mitosis resulted in the ubiquitination and degradation of Sp1. JNK1 phosphorylated Sp1 at Thr278/739. The Sp1 mutated at Thr278/739 was unstable during mitosis, possessing less transcriptional activity for the 12(S)-lipoxygenase expression and exhibiting a decreased cell growth rate compared with wild-type Sp1 in HeLa cells. In N-methyl-N-nitrosourea-induced mammary tumors, JNK1 activation provided a potential relevance with the accumulation of Sp1. Together, our results indicate that JNK1 activation is necessary to phosphorylate Sp1 and to shield Sp1 from the ubiquitin-dependent degradation pathway during mitosis in tumor cell lines.
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PMID:Phosphorylation by c-Jun NH2-terminal kinase 1 regulates the stability of transcription factor Sp1 during mitosis. 1819 80