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 anticancer effects of retinoids are mainly mediated by their nuclear receptors. Recent studies have demonstrated that retinoic acid receptor beta (RARbeta) plays a pivotal role from the early stages of laryngeal carcinogenesis; however, the exact mechanism of this detrimental effect has not yet been elucidated. One of the best-documented actions of retinoid receptors is the transrepression of activator protein-1 (AP-1) transcription factor activity, although this complex interplay has not been clarified. The present report is the first systematic morphological evaluation of the cross-talk of RARbeta and AP-1 transcription factor in a large series of human laryngeal tissues containing normal epithelium, premalignant lesions (hyperplasia and/or dysplasia) and squamous cell carcinoma. Immunohistochemical methodology was performed on formalin-fixed, paraffin-embedded sections by using a panel of monoclonal and polyclonal antibodies against RARbeta and the AP-1 components c-Jun, p-c-Jun (phosphorylated, active c-Jun) and c-Fos proteins. Their expression was screened and compared in 154 patients with various laryngeal histological entities. Nuclear expression of RARbeta, c-Jun, p-c-Jun and c-Fos was detected in 81 (89.2%), 48 (52.8%), 66 (72.6%) and 73 (80.3%), respectively, out of 91 specimens with normal-appearing laryngeal epithelium; in 86 (87.8%), 94 (95.9%), 94 (95.9%) and 94 (95.9%), respectively, out of 98 specimens with hyperplastic laryngeal epithelium; in 58 (56.8%), 92 (90.2%), 96 (94.1%) and 96 (94.1%), respectively, out of 102 specimens with dysplastic laryngeal epithelium; in 10 (22.3%), 41 (91.2%), 44 (97.8%) and 41 (91.2%), respectively, out of 45 specimens with well-differentiated squamous cell carcinoma; in 13 (30.3%), 37 (86%), 39 (90.7%) and 41 (95.3%), respectively, out of 43 specimens with moderately-differentiated squamous cell carcinoma; and in 8 (66.7%), 10 (83.3%), 12 (100%) and 12 (100%), respectively, out of 12 specimens with poorly-differentiated squamous cell laryngeal carcinoma. Statistical analysis and correlation of the intensity of nuclear immunostaining of the studied proteins among the various histological entities revealed statistically significant results. The progressive upregulation of the AP-1 transcription factor constituents and downregulation of the RARbeta protein detected from the onset of laryngeal tumorigenesis suggests an important role for the immediate-early AP-1/RARbeta on/off "switch" in the process of laryngeal carcinogenesis.
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PMID:Differential expression of retinoic acid receptor beta (RARbeta) and the AP-1 transcription factor in normal, premalignant and malignant human laryngeal tissues. 1501 78

In the absence of metastases or overgrowth to adjacent organs, the lack of reliable markers for malignancy is a well-recognized problem for clinicians managing patients with endocrine tumors. Apart from inactivation of the multiple endocrine neoplasia type 1 (MEN1) gene, the molecular mechanisms involved in tumorigenesis of the endocrine organs and MEN1-associated nonendocrine lesions are vastly unknown. To try to learn more about down-stream effects on MEN1 gene inactivation, we used the BON1 cells, showing low levels of endogenous menin, and transfected them with a MEN1 gene construct. On restoring the menin expression, we recorded inhibition of cell growth. We also performed macroarray and present data on differentially expressed genes in the transfected cells, after corroboration by Northern blots and quantitative PCR. JunD was up-regulated in menin-expressing clones, whereas delta-like protein 1/preadipocyte factor-1 (involved in differentiation and growth of the pancreatic endocrine cells), proliferating cell nuclear antigen, and QM/Jif-1 (a negative regulator of c-Jun) became down-regulated. These findings might contribute to the understanding of the tissue-specific features of MEN1. We also show that homozygous inactivation of the MEN1 gene statistically correlates to higher expression of delta-like protein 1/preadipocyte factor-1, proliferating cell nuclear antigen, and QM/Jif-1, as well as lower MEN1 expression, in a limited sample of malignant endocrine pancreatic tumors.
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PMID:Transfection of the multiple endocrine neoplasia type 1 gene to a human endocrine pancreatic tumor cell line inhibits cell growth and affects expression of JunD, delta-like protein 1/preadipocyte factor-1, proliferating cell nuclear antigen, and QM/Jif-1. 1512 60

Myc proteins regulate cell growth and division and are implicated in a wide range of human cancers. We show here that Fbw7, a component of the SCF(Fbw7) ubiquitin ligase and a tumor suppressor, promotes proteasome-dependent c-Myc turnover in vivo and c-Myc ubiquitination in vitro. Phosphorylation of c-Myc on threonine-58 (T58) by glycogen synthase kinase 3 regulates the binding of Fbw7 to c-Myc as well as Fbw7-mediated c-Myc degradation and ubiquitination. T58 is the most frequent site of c-myc mutations in lymphoma cells, and our findings suggest that c-Myc activation is one of the key oncogenic consequences of Fbw7 loss in cancer. Because Fbw7 mediates the degradation of cyclin E, Notch, and c-Jun, as well as c-Myc, the loss of Fbw7 is likely to elicit profound effects on cell proliferation during tumorigenesis.
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PMID:The Fbw7 tumor suppressor regulates glycogen synthase kinase 3 phosphorylation-dependent c-Myc protein degradation. 1518 32

Previously, no member of the mixed-lineage kinase (MLK) protein family was known to function as an oncogene. Here, we demonstrate that MLK-like mitogen-activated protein triple kinase (MLTK)-alpha, a member of the MLK family, induced neoplastic cell transformation and tumorigenesis in athymic nude mice. Introduction of small interference RNA (siRNA)-MLTK-alpha into MLTK-alpha-overexpressing cells dramatically suppressed cell transformation. Nuclear accumulation of the pHisG-MLTK-alpha fusion protein was observed after epidermal growth factor or 12-O-tetradecanoylphorbol-13-acetate treatment. Phosphorylation of downstream mitogen-activated protein kinase-targeted transcription factors including c-Myc, Elk-1, c-Jun, and activating transcription factor (ATF) 2 was also differentially enhanced in MLTK-alpha-overexpressing cells exposed to epidermal growth factor or 12-O-tetradecanoylphorbol-13-acetate stimulation compared with cells expressing mock vector or siRNA-MLTK-alpha. Very importantly, MLTK-alpha-overexpressing cells formed fibrosarcomas when injected s.c. into athymic nude mice, whereas almost no tumor formation was observed in mice that received injections of mock or siRNA-MLTK-alpha stably transfected cells. These results are the first to indicate that MLTK-alpha plays a key role in neoplastic cell transformation and cancer development.
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PMID:A novel role for mixed-lineage kinase-like mitogen-activated protein triple kinase alpha in neoplastic cell transformation and tumor development. 1517 94

The gene responsible for multiple endocrine neoplasia type 1, MEN1, encodes the 610-amino acid-protein, menin. Although menin has been reported to bind AP-1 transcription factor JunD and suppress its transcriptional activity, little is known about its molecular mechanisms and physiological role. To better understand the function of menin and its significance in tumorigenesis, we investigated the effect of wild-type and mutant menin proteins on AP-1 transactivation. In COS cells, wild-type menin suppressed JunD-mediated transactivation in a dose-dependent manner, while it augmented c-Jun-mediated transactivation also in a dose-dependent manner. These effects were lost or reduced in all menin mutants examined. Electrophoretic mobility shift assay using AP-1 binding elements as a probe revealed that menin does not affect binding of c-Jun to DNA. Coexpression of menin mutants did not affect the function of wild-type menin. Coexpression of JunD amino-terminal fragment abolished menin-mediated enhancement of c-Jun transactivation, suggesting that Menin-JunD interaction may negatively regulate the enhancing effect of menin on c-Jun-mediated transactivation in COS cells.
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PMID:JunD-menin interaction regulates c-Jun-mediated AP-1 transactivation. 1525 79

Although Jun upregulation and activation have been established as critical to oncogenesis, the relevant downstream pathways remain incompletely characterized. In this study, we found that c-Jun blocks erythroid differentiation in primary human hematopoietic progenitors and, correspondingly, that Jun factors block transcriptional activation by GATA-1, the central regulator of erythroid differentiation. Mutagenesis of c-Jun suggested that its repression of GATA-1 occurs through a transcriptional mechanism involving activation of downstream genes. We identified the hairy-enhancer-of-split-related factor HERP2 as a novel gene upregulated by c-Jun. HERP2 showed physical interaction with GATA-1 and repressed GATA-1 transcriptional activation. Furthermore, transduction of HERP2 into primary human hematopoietic progenitors inhibited erythroid differentiation. These results thus define a novel regulatory pathway linking the transcription factors c-Jun, HERP2, and GATA-1. Furthermore, these results establish a connection between the Notch signaling pathway, of which the HERP factors are a critical component, and the GATA family, which participates in programming of cellular differentiation.
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PMID:Jun blockade of erythropoiesis: role for repression of GATA-1 by HERP2. 2598 32

Mutations in the breast cancer susceptibility gene (BRCA1) account for a significant proportion of hereditary breast and ovarian cancers. Cofactor of BRCA1 (COBRA1) was isolated as a BRCA1-interacting protein and exhibited a similar chromatin reorganizing activity to that of BRCA1. However, the biological role of COBRA1 remains largely unexplored. Here, we report that ectopic expression of COBRA1 inhibited activator protein 1 (AP-1) transcriptional activity in transfected cells in a dose-dependent manner, whereas reduction of endogenous COBRA1 with a small interfering RNA significantly enhanced AP-1-mediated transcriptional activation. COBRA1 physically interacted with the AP-1 family members, c-Jun and c-Fos, and the middle region of COBRA1 bound to c-Fos. Lack of c-Fos binding site in the COBRA1 completely abolished the COBRA1 inhibition of AP-1 trans-activation. These findings suggest that COBRA1 may directly modulate AP-1 pathway and, therefore, may play important roles in cell proliferation, differentiation, apoptosis, and oncogenesis.
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PMID:COBRA1 inhibits AP-1 transcriptional activity in transfected cells. 1553 Apr 30

The FBXW7/hCDC4 gene encodes a ubiquitin ligase implicated in the control of chromosome stability. Here we identify the mouse Fbxw7 gene as a p53-dependent tumour suppressor gene by using a mammalian genetic screen for p53-dependent genes involved in tumorigenesis. Radiation-induced lymphomas from p53+/- mice, but not those from p53-/- mice, show frequent loss of heterozygosity and a 10% mutation rate of the Fbxw7 gene. Fbxw7+/- mice have greater susceptibility to radiation-induced tumorigenesis, but most tumours retain and express the wild-type allele, indicating that Fbxw7 is a haploinsufficient tumour suppressor gene. Loss of Fbxw7 alters the spectrum of tumours that develop in p53 deficient mice to include a range of tumours in epithelial tissues such as the lung, liver and ovary. Mouse embryo fibroblasts from Fbxw7-deficient mice, or wild-type mouse cells expressing Fbxw7 small interfering RNA, have higher levels of Aurora-A kinase, c-Jun and Notch4, but not of cyclin E. We propose that p53-dependent loss of Fbxw7 leads to genetic instability by mechanisms that might involve the activation of Aurora-A, providing a rationale for the early occurrence of these mutations in human cancers.
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PMID:Fbxw7/Cdc4 is a p53-dependent, haploinsufficient tumour suppressor gene. 1559 18

NF-kappaB/Rel transcription factors block apoptosis or programmed cell death (PCD) induced by tumor necrosis factor (TNF) alpha. The antiapoptotic activity of NF-kappaB is also crucial for immunity, lymphocyte development, tumorigenesis, and cancer chemoresistance. With respect to TNFalpha, the NF-kappaB-mediated suppression of apoptosis involves inhibition of the c-Jun-N-terminal kinase (JNK) cascade. This inhibitory activity of NF-kappaB depends upon transcriptional upregulation of blockers of the JNK cascade such as the caspase inhibitor XIAP, the zinc-finger protein A20, and the inhibitor of the MKK7/JNKK2 kinase Gadd45beta/Myd118. Moreover, NF-kappaB blunts accumulation of reactive oxygen species (ROS) induced by TNFalpha, and this antioxidant effect of NF-kappaB is also critical for inhibition of TNFalpha-induced JNK activation. Suppression of ROS by NF-kappaB is mediated by Ferritin heavy chain (FHC)--the primary iron-storage mechanism in cells--and possibly, by the mitochondrial enzyme Mn++ superoxide dismutase (Mn-SOD). Thus, induction of FHC and Mn-SOD represents an additional, indirect means by which NF-kappaB controls proapoptotic JNK signaling. These findings identify potential new targets for anti-inflammatory and anti-cancer therapy.
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PMID:NF-kappaB and JNK: an intricate affair. 1561 22

Nuclear factor kappaB (NF-kappaB) mediates homeostatic growth inhibition in the epidermis, and a loss of NF-kappaB function promotes proliferation and oncogenesis. To identify mechanisms responsible for these effects, we impaired NF-kappaB action in the epidermis by three different genetic approaches, including conditional NF-kappaB blockade. In each case, epidermal hyperplasia was accompanied by an increase in both protein levels and tissue distribution of the G1 cell cycle kinase, CDK4. CDK4 up-regulation required intact TNFR1 and c-Jun NH2-terminal kinase (JNK) function. Cdk4 gene deletion concomitant with conditional NF-kappaB blockade demonstrated that CDK4 is required for growth deregulation. Therefore, epidermal homeostasis depends on antagonist regulation of CDK4 expression by NF-kappaB and TNFR1/JNK.
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PMID:CDK4 regulation by TNFR1 and JNK is required for NF-kappaB-mediated epidermal growth control. 1569 16


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