Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Evidence is accumulating in support of the view that tissue-specific effects of steroid hormones depend on the recruitment of nuclear receptor comodulator proteins. The latter interact directly with the hormone receptors and modify their transcriptional effects on specific target genes. The mechanisms of comodulator influence on nuclear receptor-controlled gene transcription is only partially understood. Here, we describe the discovery of a new AR coactivator which belongs to the JmjC containing enzyme family as a novel variant of JMJD1C (jumonji domain-containing 1C). By using a fragment of the human AR (aa 325-919) as bait in a yeast two-hybrid screen, a region of the human JMJD1C gene was identified as interacting with AR. A novel splice variant s-JMJD1C was amplified by RACE, and the binding to AR was analysed by GST-pull-down and mammalian one-hybrid experiments. As a nuclear-localized protein, the s-JMJD1C gene is expressed in a variety of human tissues. In the brain, this protein is present in several, but not confined to, AR-expressing neuronal populations and its abundance varies with the hormonal status in a region-specific fashion. Interestingly, the expression of s-JMJD1C is reduced in breast cancer tumors and significantly higher in normal breast tissues indicating a putative role in tumor suppression. As s-JMJD1C has putative demethylase activity, removal of methylation seems to be important for nuclear receptor-based gene regulation.
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PMID:A novel variant of the putative demethylase gene, s-JMJD1C, is a coactivator of the AR. 1735 3

Posttranslational modification of chromatin by histone methylation has wide-ranging effects on nuclear function, including transcriptional regulation, maintenance of genome integrity, and epigenetic inheritance. The enzymes utilized to place histone methylation marks are well characterized, but the identity of a histone demethylation system remained elusive until recently. The discovery of histone demethylase enzymes capable of directly removing methyl groups from modified lysine residues has demonstrated that histone methylation is a dynamic modification. The most extensive family of histone demethylase enzymes identified so far contains a JmjC domain and catalyzes demethylation through a hydroxylation reaction. Here, we identify PLU-1, a transcriptional repressor implicated in breast cancer, as a histone demethylase enzyme that has the ability to reverse the trimethyl H3K4 modification state. Furthermore, we reveal that PLU-1-mediated H3K4 demethylase activity plays an important role in the proliferative capacity of breast cancer cells through repression of tumor suppressor genes, including BRCA1.
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PMID:PLU-1 is an H3K4 demethylase involved in transcriptional repression and breast cancer cell proliferation. 1736 12

Epigenetic regulation of transcription refers to reversible, heritable changes in gene expression that occur in the absence of changes in DNA sequence. A major epigenetic mechanism involves the covalent modification of nucleosomal histones to create binding sites for transcriptional regulators and chromatin remodeling complexes that mediate activation or repression of transcription. While it has been known for a number of years that many histone modifications are reversible, it has only recently been shown that methyl groups are enzymatically removed from lysine residues. Here we discuss the recent characterization of a new class of demethylase enzyme, the JARID1 family, which catalyzes the removal of methyl groups from lysine 4 of histone H3. We summarize recent findings regarding the function of this family of proteins, focusing on our characterization of Little imaginal discs (Lid), the sole JARID1 family protein in Drosophila, which is rate-limiting for Myc-induced cell growth. Finally, we propose models to explain the role of Lid in Myc-mediated growth and discuss the relevance of these findings to human disease and tumor formation.
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PMID:The function and regulation of the JARID1 family of histone H3 lysine 4 demethylases: the Myc connection. 1756 93

Histone modifications, such as acetylation and methylation, are important epigenetic marks that regulate diverse biological processes that use chromatin as the template, including transcription. Dysregulation of histone acetylation and methylation leads to the silencing of tumor suppressor genes and contributes to cancer progression. Inhibitors of enzymes that catalyze the addition and removal of these epigenetic marks thus have therapeutic potential for treating cancer. Lysine-specific demethylase 1 (LSD1) is the first discovered histone lysine demethylase and, with the help of its cofactor CoREST, specifically demethylates mono- and dimethylated histone H3 lysine 4 (H3-K4), thus repressing transcription. Because LSD1 belongs to the family of flavin adenine dinucleotide (FAD)-dependent amine oxidases, certain inhibitors of monoamine oxidases (MAOs), including the clinically used antidepressant trans-2-phenylcyclopropylamine (PCPA; tranylcypromine; Parnate), are also capable of inhibiting LSD1. In this study, we have further measured the kinetic parameters of the inhibition of LSD1 by PCPA and determined the crystal structure of LSD1-CoREST in the presence of PCPA. Our structural and mass spectrometry analyses are consistent with PCPA forming a covalent adduct with FAD in LSD1 that is distinct from the FAD-PCPA adduct of MAO B. The structure also reveals that the phenyl ring of the FAD-PCPA adduct in LSD1 does not form extensive interactions with active-site residues. This study thus provides the basis for designing more potent inhibitors of LSD1 that contain substitutions on the phenyl ring of PCPA to fully engage neighboring residues.
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PMID:Structural basis for the inhibition of the LSD1 histone demethylase by the antidepressant trans-2-phenylcyclopropylamine. 1756 9

SMCX/JARID1C was recently shown to be a histone H3 lysine 4 (H3K4) demethylase. Here, we have identified an SMCX isoform that predominantly resides in the cytoplasm, but still efficiently demethylates trimethylated H3K4. SMCX requires several functional domains for its demethylase activity and is also capable of forming homomers through amino acids 204-493. Further, SMCX physically interacts with Smad3, a mediator of transforming growth factor-beta (TGF-beta), and overexpression of SMCX inhibits the ability of Smad3 to activate transcription. Thus, SMCX is a novel Smad3 corepressor that may antagonize the tumor suppressing activity of the TGF-beta/Smad3 signaling pathway and thereby contribute to tumorigenesis. Indeed, SMCX is overexpressed in prostate tumors and seminomas, suggesting that SMCX might be a novel oncogene.
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PMID:Repression of Smad3 activity by histone demethylase SMCX/JARID1C. 1807 10

Expression of BIRC5 (survivin), a member of the inhibitor of apoptosis protein (IAP) family, is elevated in fetal tissues and in various human cancers. Mechanisms up-regulating BIRC5 in cancer are poorly understood. Here, we show that overexpression of BIRC5 induces a high proliferation level in MCF-7 breast tumor cells. In a population of 191 breast carcinomas, BIRC5 expression is not affected by BIRC5 promoter polymorphism at -31, or BIRC5 gene copy number. However, a significant correlation was found between expression of demethylase (dMTase) and expression of BIRC5. In addition, among 13 chromosomal regions tested for allelic loss [loss of heterozygosity (LOH)], two regions close to D3S1478 and D6S264 were related to BIRC5 expression. In tumors with LOH at D3S1478 and/or D6S264, BIRC5 expression was significantly increased. These regions have been suggested to harbor tumor suppressor genes and/or common fragile sites that may play a role in increasing genetic instability. These results suggest that genes located near D3S1478 and D6S264 might work by inhibiting, directly or indirectly, BIRC5 expression and thus their loss leads to its up-regulation. In addition, BIRC5 expression may induce breast tumor proliferation by promoting genetic instability. This article contains Supplementary Material available at http://www.interscience.wiley.com/jpages/1045-2257/suppmat.
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PMID:The expression of BIRC5 is correlated with loss of specific chromosomal regions in breast carcinomas. 1818 Nov 75

Myelodysplastic syndrome is a hematopoietic stem cell disorder characterized by ineffective hematopoiesis and leukemic progression. Accumulation of various kinds of genetic alterations in oncogene and tumor suppressor gene develops and accelerates the disease. Recently, alpha-catenin gene has been identified as a candidate gene in the 5q- anomaly. Diagnostic criteria have been updated by Valent et al. WHO classification has become popular and WHO classification-based prognostic scoring system will be employed to evaluate prognosis. In our country, clinical studies on vitamin K2+D3 and cyclosporine A were conducted in low-risk patients, and their efficacy and safety have been reported. In US, molecular-targeting therapy with lenalidomide or demethylase is approved by FDA.
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PMID:[Myelodysplastic syndrome]. 1833 27

The tumor suppressor p53 is the most frequently inactivated gene in human cancers. The p53 protein functions as a sequence-specific transcription factor to regulate key cellular processes, including cell-cycle arrest, DNA repair, apoptosis, and senescence in response to stress signals. P53 is maintained at a low level in the cell, but becomes rapidly stabilized and activated in response to DNA damage, hypoxia, hyperproliferation, and other types of cellular stresses. The stability and transcriptional activity of p53 are tightly regulated through multiple post-translational modifications, such as phosphorylation, acetylation, and ubiquitination. Within the past few years, several studies have established that protein methylation is a novel mechanism by which p53 is regulated. Indeed, histone lysine methyltransferases KMT5 (Set9), KMT3C (Smyd2), and KMT5A (Set8) methylate p53 at specific C-terminal lysines. Lysine methylation enhances or suppresses p53 transcriptional activity depending on the methylation site. Furthermore, the lysine-specific demethylase KDM1 (LSD1) mediates p53 demethylation, which prevents p53 interaction with its co-activator 53BP1 to induce apoptosis. Finally, protein arginine methyltransferases CARM1 and PRMT1 are co-activators of p53 involved in the methylation of histones H3 and H4 to facilitate p53-mediated transcription. In response to cellular stresses, the interplay between p53 methylation, demethylation, and other post-translational modifications fine-tunes the activity of p53 to ultimately prevent tumor formation.
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PMID:Protein methylation: a new mechanism of p53 tumor suppressor regulation. 1858 Dec 85

Hormone signaling is important in a number of disease states, and hormone receptors are effective therapeutic targets. PGRMC1 (progesterone receptor membrane component 1) is a member of a multi-protein complex that binds to progesterone and other steroids, as well as pharmaceutical compounds. In spite of its name, PGRMC1 shares homology with cytochrome b5-related proteins rather than hormone receptors, and heme binding is the sole biochemical activity of PGRMC1. PGRMC1 and its homologues regulate cholesterol synthesis by activating the P450 protein Cyp51/lanosterol demethylase, and the cholesterol synthetic pathway is an important target in cardiovascular disease and in treating infections. PGRMC1 binding partners include multiple P450 proteins, PAIR-BP1, Insig, and an uncharacterized hormone/drug-binding protein. PGRMC1 is induced in a spectrum of cancers, where it promotes cell survival and damage resistance, and PGRMC1 is also expressed in the nervous system and tissues involved in drug metabolism, cholesterol synthesis and hormone synthesis and turnover. One of the appealing features of PGRMC1 and its associated protein complex is its affinity for steroids and drugs. Together with its biological role in promoting tumor survival, PGRMC1 is an attractive target for therapeutic intervention in cancer and related malignancies.
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PMID:PGRMC1 (progesterone receptor membrane component 1): a targetable protein with multiple functions in steroid signaling, P450 activation and drug binding. 1899 68

Somatically acquired epigenetic changes are present in many cancers. Epigenetic regulation is maintained via post-translational modifications of core histones. Here, we describe inactivating somatic mutations in the histone lysine demethylase gene UTX, pointing to histone H3 lysine methylation deregulation in multiple tumor types. UTX reintroduction into cancer cells with inactivating UTX mutations resulted in slowing of proliferation and marked transcriptional changes. These data identify UTX as a new human cancer gene.
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PMID:Somatic mutations of the histone H3K27 demethylase gene UTX in human cancer. 1933 29


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