Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

TNFR-associated factors (TRAFs) participate in diverse biological processes, such as adaptive and innate immunity, stress response, and bone metabolism. We report that all TRAFs except TRAF3 are expressed at mRNA and protein levels in B cell-derived Hodgkin's lymphoma cell lines (L428 and KM-H2). Both the classical (p50-RelA) and the alternative NF-kappaB activity (p52-RelB) are sustained in L428 and KM-H2 cells. A successful depletion of TRAF1 protein expression by means of RNA interference abrogates the anti-apoptosis activity in L428 cells. The TRAF1-deficiency reduces the classical NF-kappaB activity but not the alternative activity. The expression of the NF-kappaB targeting genes, such as ICAM-1, c-Flip, and Cyclin D1, is suppressed in the TRAF1-depleted cells. On the other hand, CD30 signaling upregulates the TRAF1 expression while reducing the expression of TRAF2 and TRAF5. Importantly, the CD30-induced alternative NF-kappaB activation is inhibited by the depletion of the TRAF1 expression. We also demonstrate that the phosphorylation of the extracellular signal-regulated kinase (ERK) upon CD30 stimulation in Hodgkin's lymphoma cells is independent of TRAF1 expression. Our data shed new light on the function of TRAF1 in B cell-derived lymphoma cells. We conclude that TRAF1 is an important molecule mediating both the CD30 signaling-dependent and independent NF-kappaB activation, which prevents the lymphoma cells from spontaneous and induced apoptosis.
Mol Immunol 2009 Aug
PMID:TRAF1 is involved in the classical NF-kappaB activation and CD30-induced alternative activity in Hodgkin's lymphoma cells. 1954 May 95

There is growing evidence for a connection between inflammation and tumor development, and the nuclear factor kappa B (NF-kappaB), a proinflammatory transcription factor, is hypothesized to promote tumorigenesis. Although the genetic evidence for the hypothesis has been lacking, recent papers have lent credence to this hypothesis. It has been reported that constitutive NF-kappaB activation in inflammatory bowel diseases (IBDs) increases risk of colorectal cancer (CRC) in the patients with the number of years of active disease. NF-kappaB activation might induce cellular transformation, mediate cellular proliferation, prevent the elimination of pre-neoplastic and fully malignant cells by up-regulating the anti-apoptosis proteins. Furthermore, NF-kappaB may contribute to the progression of CRC by regulating the expression of diverse target genes that are involved in cell proliferation (Cyclin D1), angiogenesis (VEGF, IL-8, COX2), and metastasis (MMP9). These findings implicate NF-kappaB inhibition as an important therapeutic target in CRC. However, due to lack of knowledge about the specific roles of different NF-kappaB subunits in different stage of carcinogenesis, and compounds to block specific subunits of NF-kappaB family, it will be a long time before the coming of targeting NF-kappaB in CRC therapy.
Cell Mol Immunol 2009 Oct
PMID:NF-kappaB signaling pathway, inflammation and colorectal cancer. 1988 45

Nonsteroidal anti-inflammatory drugs (NSAIDs) can inhibit cell growth and metastasis, and induce cell apoptosis in cancerous cells. They have been shown to reduce incidence and mortality of gastric cancer by an unknown mechanism. NSAIDs often exert their effects by Cox-2 inhibition, and Cox-2 is overexpressed in gastric cancer cells. Nevertheless, when gastric cancer cells were treated with different NSAIDs, the non-Cox-2-inhibiting R-flurbiprofen was most effective at reducing proliferation of gastric cancer cells in vitro. R-Flurbiprofen prevented the metastatic characteristics of gastric cancer cells in vitro, and reduced tumor size and metastasis in vitro, when gastric cancer cells were injected into nude mice. R-Flurbiprofen also affected multidrug resistance, increasing the sensitivity of resistant gastric cancer cells to chemotherapeutic agents. Mechanistically, R-flurbiprofen was found to have pleiotropic effects, changing levels of cell cycle factors like Cyclin D1 and CKD4, apoptotic protwins like caspase3 and Bcl-2, and protwins that affect metastasis, like metalloproteases. Consistent with reports on other cancer cell types, NSAID treatment with R-flurbiprofen increased levels of the tumor suppressor neurotrophin receptor (p75(NTR)) in gastric cancer cells. The anticancer effects of R-flurbiprofen were found to require induction of p75(NTR) via the p38 signaling pathway, suggesting a possible mechanism of action.
Mol Pharm 2010 Feb 01
PMID:R-flurbiprofen reverses multidrug resistance, proliferation and metastasis in gastric cancer cells by p75(NTR) induction. 1991 60

Cyclin D1 is involved in regulating the transition of G1 to S-phase in the cell cycle through phosphorylation of the retinoblastoma susceptibility product (pRB). Amplification and overexpression of the cyclin D1 gene (CCND1) have been reported in human breast cancers and are suggested to play important roles in the pathogenesis of the disease process. Although cyclin D1 is potentially an important gene, relatively little is known about the distribution of its amplification in breast cancer cell lines. In this study, a cyclin D1 cosmid probe was isolated and used with fluorescence in situ hybridization (FISH) to identify the gene in chromosomal spreads of 12 breast cancer cell lines. Nine cell lines showed increased gene copy levels of cyclin D1, including Five cell lines had more than six copies of cyclin D1 on sister chromatids and four had more than four copies but less than six copies grouped at the chromosome 11 q13 band. Three cell lines had two "normal" chromosome 11 and one and two additional derivative chromosome 11's with three and four 11q13 sites which lacked amplification of cyclin D1 on any of these sites. Using progesterone receptor (PR) gene as an internal control, a 2.0-fold or greater increase in cyclin D1 gene signals, was observed in five of the ten cell lines by Southern hybridization, the Amplification level of cyclin D1 varied from 2.3 to 19.6-fold. Three cell lines with low amplification of cyclin D1 showed overexpression of the gene by Northern analysis. Our experiments demonstrated that FISH was more sensitive than Southern blot at demonstrating low levels of gene amplification and, additionally, permitted assessment of the distribution of cyclin D1 gene among chromosomes.
Mol Biol Rep 2010 Oct
PMID:FISH is more sensitive than Southern analysis at identifying increased levels of cyclin D1 gene amplified in breast cancer cell lines. 1996 53

Medulloblastoma is an aggressive primary brain tumor that arises in the cerebellum of children and young adults. The Sonic Hedgehog (Shh) signaling pathway that plays important roles in the pathology of this aggressive disease is a promising therapeutic target. In the present report we have shown that curcumin has cytotoxic effects on medulloblastoma cells. Curcumin suppressed also cell proliferation and triggered cell-cycle arrest at G(2)/M phase. Moreover, curcumin inhibited the Shh-Gli1 signaling pathway by downregulating the Shh protein and its most important downstream targets GLI1 and PTCH1. Furthermore, curcumin reduced the levels of beta-catenin, the activate/phosphorylated form of Akt and NF-kappaB, which led to downregulating the three common key effectors, namely C-myc, N-myc, and Cyclin D1. Consequently, apoptosis was triggered by curcumin through the mitochondrial pathway via downregulation of Bcl-2, a downstream anti-apoptotic effector of the Shh signaling. Importantly, the resistant cells that exhibited no decrease in the levels of Shh and Bcl-2, were sensitized to curcumin by the addition of the Shh antagonist, cyclopamine. Furthermore, we have shown that curcumin enhances the killing efficiency of nontoxic doses of cisplatin and gamma-rays. In addition, we present clear evidence that piperine, an enhancer of curcumin bioavailability in humans, potentiates the apoptotic effect of curcumin against medulloblastoma cells. This effect was mediated through strong downregulation of Bcl-2. These results indicate that curcumin, a natural nontoxic compound, represents great promise as Shh-targeted therapy for medulloblastomas.
Mol Carcinog 2010 Mar
PMID:Curcumin inhibits the Sonic Hedgehog signaling pathway and triggers apoptosis in medulloblastoma cells. 2002 76

Comparative proteomics was performed to identify proteins in the liver of Takifugu rubripes in response to excessive fluoride exposure. Sixteen fish were randomly divided into a control group and an experimental group. The control group was raised in soft water alone (F(-) = 0.4 mg/L), and the experimental group was raised in the same water with sodium fluoride at a high concentration of 35 mg/L. After 3 days, proteins were extracted from the fish livers and then subjected to two-dimensional polyacrylamide gel electrophoresis analysis. The matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS) was applied to identify the proteins that were differentially expressed from the two groups of fish. Among an average of 816 and 918 proteins detected in the control and treated groups, respectively, 16 proteins were upregulated and 35 were downregulated (P < 0.01) in the fluoride-treated group as compared with those in the control group. Twenty-four highly differentially expressed proteins were further analyzed by MALDI-TOF/TOF-MS, and eight were identified by Mascot. These eight proteins include disulfide isomerase ER-60, 4SNc-Tudor domain protein, SMC3 protein, Cyclin D1, and mitogen-activated protein kinase 10, as well as three unknown proteins. Consistent with their previously known functions, these identified proteins seem to be involved in apoptosis and other functions associated with fluorosis. These results will greatly contribute to our understanding of the effects of fluoride exposure on the physiological and biochemical functions of Takifugu and the toxicological mechanism of fluoride causing fluorosis in both fish and human.
J Biochem Mol Toxicol
PMID:Proteomics analysis of liver samples from puffer fish Takifugu rubripes exposed to excessive fluoride: an insight into molecular response to fluorosis. 2014 79

Estrogen and progesterone are the defining hormones of normal female development, and both play critical roles in breast carcinogenesis. Cyclin D1 is a breast cancer oncogene whose amplification is linked to poor prognosis in estrogen and progesterone receptor-positive breast cancers. Here we report that cyclin D1 regulates progesterone receptor expression, consequently enhancing responses to estrogen and progesterone. Estrogen treatment of cyclin D1 transgenic mice increased progesterone receptor expression and induced mammary hyperplasias that were stimulated by progesterone and blocked by a progesterone antagonist. Progesterone receptor levels decreased in cyclin D1 knockout mice. Cyclin D1 regulated progesterone receptor expression through a novel estrogen- and cyclin D1-responsive enhancer in DNA encoding part of the 3' untranslated region of the progesterone receptor gene. Small inhibitory RNAs for cyclin D1 decreased progesterone receptor expression and estrogen receptor binding to the 3' enhancer region in human breast cancer cells. Since estrogen and progesterone regulate cyclin D1, our results suggest that cyclin D1's participation in a feed-forward loop could contribute to increased breast cancer risks associated with estrogen and progesterone combinations. Additionally, its regulation of the progesterone receptor identifies a novel role for cyclin D1 in ovarian hormone control of breast development and breast carcinogenesis.
Mol Cell Biol 2010 Jun
PMID:Cyclin D1 enhances the response to estrogen and progesterone by regulating progesterone receptor expression. 2040 95

Although stem cells can proliferate and differentiate through the completion of cell cycle progression, little is known about the genes and molecular mechanisms controlling this process. Here, we investigated the effect of the inhibition of cell cycle by cyclin D1 gene knockout on proliferation and differentiation of neural stem cells (NSCs). Knockout of cyclin D1 induced the cultured neural stem cells arrested at the G0/G1 phase as detected by flow cytometry. Cyclin D1 knockout led to the apoptosis of NSCs and inhibited the differentiation into astrocytes without affecting the differentiation into neurons. We further demonstrated that a significant reduction of BrdU+ cells in the subgranular zone of the dentate gyrus and subventricular zone was found in cyclin D1 gene knockout (cyclin D1(-/-)) mice compared with cyclin D1(+/+) and cyclin D1(+/-) mice. These observations demonstrated that cyclin D1 plays essential roles in the proliferation and differentiation of neural stem cells.
J Mol Neurosci 2010 Sep
PMID:Proliferation and differentiation of neural stem cells are selectively regulated by knockout of cyclin D1. 2043 10

While much is known about the deleterious effects of pro-inflammatory cytokines on development of vascular disease, little is reported on the direct effects of anti-inflammatory cytokines on the vascular smooth muscle cell (VSMC) response to injury. Interleukin-19 (IL-19) is a recently described Th2, anti-inflammatory interleukin. We have previously reported that IL-19 is absent in normal VSMC, but induced in VSMC by inflammatory cytokines and in arteries by injury. IL-19 is anti-proliferative for VSMC. The purpose of this study is to determine the molecular mechanism of these effects. In cultured, primary human VSMC, IL-19 reduces abundance of proliferative and inflammatory gene proteins and mRNA, including Cyclin D1, IL-1beta, IL-8, and COX2. IL-19 does not inhibit NF-kappaB, but does transiently reduce cytoplasmic abundance of the mRNA stability factor HuR. The mRNA stabilizing function of HuR is linked to its phosphorylation and cytoplasmic translocation. IL-19 reduces serine phosphorylation of HuR, and activation of PKCalpha, a known regulator of HuR translocation. Actinomycin D transcription blockade demonstrates that IL-19 treatment significantly reduces stability of proliferative and inflammatory mRNAs. Knock down of HuR with siRNA also reduces stability of these inflammatory mRNA transcripts. These data indicate that IL-19 has direct effects on VSMC mRNA stability. One potential mechanism whereby IL-19 reduces the VSMC response to injury is by regulation of HuR abundance and cytoplasmic translocation, with a subsequent decrease in mRNA half-life of proliferative and inflammatory mRNA transcripts.
J Mol Cell Cardiol 2010 Oct
PMID:Il-19 reduces VSMC activation by regulation of mRNA regulatory factor HuR and reduction of mRNA stability. 2045 30

The tumor suppressor gene HIC1 encodes a transcriptional repressor involved in regulatory loops modulating P53-dependent and E2F1-dependent cell survival, growth control, and stress responses. Despite its importance, few HIC1 corepressors and target genes have been characterized thus far. Using a yeast two-hybrid approach, we identify MTA1, a subunit of the NuRD complex, as a new HIC1 corepressor. This interaction is regulated by two competitive posttranslational modifications of HIC1 at lysine 314, promotion by SUMOylation, and inhibition by acetylation. Consistent with the role of HIC1 in growth control, we demonstrate that HIC1/MTA1 complexes bind on two new target genes, Cyclin D1 and p57KIP2 in quiescent but not in growing WI38 cells. In addition, HIC1/MTA1 and HIC1/CtBP complexes differentially bind on two mutually exclusive HIC1 binding sites (HiRE) on the SIRT1 promoter. SIRT1 transcriptional activation induced by short-term serum starvation coincides with loss of occupancy of the distal sites by HIC1/MTA1 and HIC1/CtBP. Upon longer starvation, both complexes are found but on a newly identified proximal HiRE that is evolutionarily conserved and specifically enriched with repressive histone marks. Our results decipher a mechanistic link between two competitive posttranslational modifications of HIC1 and corepressor recruitment to specific genes, leading to growth control.
Mol Cell Biol 2010 Aug
PMID:Differential regulation of HIC1 target genes by CtBP and NuRD, via an acetylation/SUMOylation switch, in quiescent versus proliferating cells. 2054 55


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