Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P51532 (transcriptional activator)
 6,546 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Signaling-protein mRNAs tend to have long untranslated regions (UTRs) containing binding sites for RNA-binding proteins regulating gene expression. Here we show that a PUF-family RNA-binding protein, Mpt5, represses the yeast MAP-kinase pathway controlling differentiation to the filamentous form. Mpt5 represses the protein levels of two pathway components, the Ste7 MAP-kinase kinase and the Tec1 transcriptional activator, and negatively regulates the kinase activity of the Kss1 MAP kinase. Moreover, Mpt5 specifically inhibits the output of the pathway in the absence of stimuli, and thereby prevents inappropriate cell differentiation. The results provide an example of what may be a genome-scale level of regulation at the interface of signaling networks and protein-RNA binding networks.
 ...
PMID:Control of signaling in a MAP-kinase pathway by an RNA-binding protein. 1732 13

It has been reported that mouse Lbh (limb-bud and heart) can regulate cardiac gene expression by modulating the combinatorial activities of key cardiac transcription factors, as well as their individual functions in cardiogenesis. Here we report the cloning and characterization of the human homolog of mouse Lbh gene, hLBH, from a human embryonic heart cDNA library. The cDNA of hLBH is 2927 bp long, encoding a protein product of 105 amino acids. The protein is highly conserved in evolution across different species from zebra fish, to mouse, to human. Northern blot analysis indicates that a 2.9 kb transcript specific for hLBH is most abundantly expressed in both embryonic and adult heart tissue. In COS-7 cells, hLBH proteins are localized to both the nucleus and the cytoplasm. hLBH is a transcription activator when fused to Gal-4 DNA-binding domain. Deletion analysis indicates that both the N-terminal containing proline-dependent serine/threonine kinase group and the C-terminal containing ERK D-domain motif are required for transcriptional activation. Overexpression of hLBH in COS-7 cells activates the transcriptional activities of activator protein-1 (AP-1) and serum response element (SRE). These results suggest that hLBH proteins may act as a transcriptional activator in mitogen-activated protein kinase signaling pathway to mediate cellular functions.
 ...
PMID:A human homolog of mouse Lbh gene, hLBH, expresses in heart and activates SRE and AP-1 mediated MAPK signaling pathway. 1739 Feb 36

Transcription factor E2F-1 mediates apoptosis and suppresses tumorigenesis. The mechanisms by which E2F-1 functions in these processes are largely unclear. We report here that E2F-1 acts as a transcriptional regulator of MKP-2 (MAPK phosphatase-2), a dual specificity protein phosphatase (DUSP4) with stringent substrate specificity for MAPKs. We show that E2F-1 is required for the cellular apoptotic response to oxidative damage. MKP-2 is greatly increased following oxidative stress, and E2F-1 is necessary for that induction. We found that E2F-1 is physically associated with the MKP-2 promoter and can transactivate the promoter of the MKP-2 gene. Specifically, E2F-1 binds to a perfect palindromic motif in the MKP-2 promoter. Finally, we show that this E2F-1/MKP-2 pathway mediates apoptosis under oxidative stress and that MKP-2 suppresses tumor formation in nude mice. Our findings demonstrate that E2F-1 is a transcriptional activator of MKP-2 and that MKP-2 is an essential cell death mediator in the E2F-1 pathway. Characterization of MKP-2 as a cell death mediator may lead to the development of new strategies for cancer treatment.
 ...
PMID:A molecular link between E2F-1 and the MAPK cascade. 1745 31

The pathology of joint destruction is associated with elevated production of basic fibroblast growth factor (bFGF) and matrix metalloproteinase-13 (MMP-13). In osteoarthritic joint disease, expression of bFGF and MMP-13 in chondrocytes and their release into the synovial fluid are significantly increased. We have previously found that the capacity for cartilage repair in human adult articular chondrocytes is severely compromised by minimal exposure to bFGF because bFGF reduces responsiveness to bone morphogenetic protein-7 and insulin-like growth factor-1 and induces MMP-13 through protein kinase Cdelta-dependent activation of multiple mitogen-activated protein kinase (MAPK) signaling pathways. Here we show using biochemical and molecular approaches that transcription factor Elk-1, a direct downstream target of MAPK, is a critical transcriptional activator of of MMP-13 by bFGF in human articular chondrocytes. We also provide evidence that Elk-1 is a direct target of NFkappaB and induces MMP-13 expression upon activation of the NFkappaB signaling pathway. Taken together, our results suggest that elevated expression of MMP-13 occurs through Elk-1 activation of both MAPK and NFkappaB signaling pathways, thus revealing a two-pronged biological mechanism by which bFGF controls the production of catabolic enzymes that are associated with excessive degradation of the cartilage matrix in degenerative joint diseases such as osteoarthritis.
 ...
PMID:Basic fibroblast growth factor activates the MAPK and NFkappaB pathways that converge on Elk-1 to control production of matrix metalloproteinase-13 by human adult articular chondrocytes. 1772 16

The budding yeast, Saccharomyces cerevisiae, responds to various environmental cues by invoking specific adaptive mechanisms for their survival. Under nitrogen limitation, S. cerevisiae undergoes a dimorphic filamentous transition called pseudohyphae, which helps the cell to forage for nutrients and reach an environment conducive for growth. This transition is governed by a complex network of signaling pathways, namely cAMP-PKA, MAPK and TOR, which controls the transcriptional activation of FLO11, a flocculin gene that encodes a cell wall protein. However, little is known about how these pathways co-ordinate to govern the conversion of nutritional availability into gene expression. Here, we have analyzed an integrative network comprised of cAMP-PKA, MAPK and TOR pathways with respect to the availability of nitrogen source using experimental and steady state modeling approach. Our experiments demonstrate that the steady state expression of FLO11 was bistable over a range of inducing ammonium sulphate concentration based on the preculturing condition. We also show that yeast switched from FLO11 expression to accumulation of trehalose, a STRE response controlled by a transcriptional activator Msn2/4, with decrease in the inducing concentration to complete starvation. Steady state analysis of the integrative network revealed the relationship between the environment, signaling cascades and the expression of FLO11. We demonstrate that the double negative feedback loop in TOR pathway can elicit a bistable response, to differentiate between vegetative growth, filamentous growth and STRE response. Negative feedback on TOR pathway function to restrict the expression of FLO11 under nitrogen starved condition and also with re-addition of nitrogen to starved cells. In general, we show that these global signaling pathways respond with specific sensitivity to regulate the expression of FLO11 under nitrogen limitation. The holistic steady state modeling approach of the integrative network revealed how the global signaling pathways could differentiate between multiple phenotypes.
 ...
PMID:Integration of global signaling pathways, cAMP-PKA, MAPK and TOR in the regulation of FLO11. 1830 41

Hypoxia-inducible factor 1 (HIF-1) is the key transcriptional activator of hypoxia-inducible genes and an important anti-cancer target. Its regulated subunit, HIF-1alpha, is controlled by oxygen levels and major signaling pathways. We reported previously that phosphorylation of Ser(641/643) by p42/44 MAPK is essential for HIF-1alpha nuclear accumulation and activity. We now show that a fragment of HIF-1alpha (amino acids 616-658), termed MAPK target domain, contains a nuclear export signal (NES), which has atypical hydrophobic residue spacing. Localization, reporter gene, and co-immunoprecipitation assays demonstrate that the identified NES interacts with CRM1 in a phosphorylation-sensitive manner. Furthermore, disruption of the NES (I637A/L638A/I639A) restores nuclear localization and activity of nonphosphorylated HIF-1alpha and renders it largely resistant to inhibition of MAPK, an effect reproduced by a phosphomimetic mutation (S641E). As these data predict, overexpression of wild-type or mutant (S641A/S643A) MAPK target domain in HeLa cells modulates the activity and subcellular distribution of endogenous HIF-1alpha. We suggest that control of HIF-1alpha nuclear transport represents an important MAPK-dependent regulatory mechanism.
 ...
PMID:Atypical CRM1-dependent nuclear export signal mediates regulation of hypoxia-inducible factor-1alpha by MAPK. 1868 85

The activity of nuclear transcription factors is often regulated by specific kinase-signaling pathways. We have previously shown that the organochlorine pesticide dichlorodiphenyltrichloroethane (DDT) stimulates activator protein-1 activity through the p38 mitogen-activated protein kinase (MAPK). Here, we show that DDT and its metabolites also stimulate the transcriptional activity of cyclic adenosine monophosphate response element-binding protein and Elk1 and potentiate gene expression through cyclic adenosine monophosphate and hypoxia response elements. Because DDT stimulates gene expression through various transcription factors and hence multiple response elements, we hypothesized that p38 signaling targets a common shared transcriptional activator. Here, we demonstrate using both pharmacological and molecular techniques, the general coactivator p300 is phosphorylated and potentiated by the p38 MAPK signaling cascade. We further show that p38 directly phosphorylates p300 in its N-terminus. These results, together with our previous work, suggest that p38 stimulates downstream transcription factors in part by targeting the general coactivator p300.
 ...
PMID:Organochlorine-mediated potentiation of the general coactivator p300 through p38 mitogen-activated protein kinase. 1879 Dec

In budding yeast, elements of a single MAP Kinase cascade are shared to regulate a wide range of functions such as mating, differentiation and osmotic stress. However, cells have programmed to execute correct event in response to a given input signal without cross activating other responses. Studies have observed that magnitude and duration of MAPK activation encodes specificity. Similarly, the differential regulation of Tec1p, a transcriptional activator of invasive growth gene, FLO11 by MAP kinases has been observed to bring specificity in mating and invasive growth signaling. However, the understanding of interactions between the shared components and other signaling pathways related to the phenotypic response in contributing towards specificity remains unclear. We specifically address the crosstalk of cAMP pathway with MAPK pathway in haploid invasive growth and show the contribution and importance of cAMP pathway towards invasive growth irrespective of the activation status of MAPK pathway. Our analysis shows that crosstalk from cAMP pathway in haploids might offer an advantage in terms of amplifying the observed weak signaling through MAPK pathway. Further, we show that such a crosstalk in haploids leads to higher FLO11 expression than diploids. We also demonstrate the positive and negative role of Tpk1 and Tpk3 in haploid invasive growth. Finally, we observe that a cross-inhibition at gene level brought about by cAMP pathway controlled inhibitor, Sfl1, perhaps help in deamplifying the MAPK signal and also in preventing FLO11 expression in the absence of cAMP pathway activation.
 ...
PMID:Specificity of MAPK signaling towards FLO11 expression is established by crosstalk from cAMP pathway. 1900 39

Occurrence of multiple upstream activation sites (UASs) is a structural motif that is observed within the promoter of eukaryotic genes for coordinating gene expression. Transcriptional activation depends on the ability of transcriptional activators to bind to its specific UASs, which are kept inaccessible due to the nucleosomal organization of the chromatin. Targeting of chromatin remodeling complexes by a sequence specific transcriptional activator is shown to be detrimental for transcriptional initiation. Here, we analyze such a regulatory structure involving ordered recruitment of transcriptional activators and chromatin remodeling complexes with respect to activation of a flocculin gene, FLO11 involved in the filamentous growth to gain insights into its regulation. We develop a steady state model for the transcriptional regulation of FLO11 by primary transcriptional activators Flo8p, Ste12p, Tec1p and Mss11p, which are under a complex network comprising of cAMP and MAPK pathways. Our analysis predicts that the FLO11 promoter should undergo varying chromatin remodeling activity from partial to complete disassembly depending upon the concentration of Ste12p. This variation should be sensitive and sharply shift to saturate with Ste12p concentration. Overexpression of Ste12p can increase the overall chromatin remodeling activity by increasing the local concentration of remodeling complex through active recruitment. Further, we demonstrate that the chromatin remodeling activity brings about amplification of cAMP and MAPK signal and in absence of either of the signals, the input signal required for the other increases. We also discuss the results obtained from our steady state analysis in respect to other eukaryotic genes.
 ...
PMID:A steady state model for the transcriptional regulation of filamentous growth in Saccharomyces cerevisiae. 1903 57

Type 3 (T3) effector proteins, secreted by nitrogen-fixing rhizobia with a bacterial T3 secretion system, affect the nodulation of certain host legumes. The open reading frame y4lO of Rhizobium sp. strain NGR234 encodes a protein with sequence similarities to T3 effectors from pathogenic bacteria (the YopJ effector family). Transcription studies showed that the promoter activity of y4lO depended on the transcriptional activator TtsI. Recombinant Y4lO protein expressed in Escherichia coli did not acetylate two representative mitogen-activated protein kinase kinases (human MKK6 and MKK1 from Medicago truncatula), indicating that YopJ-like proteins differ with respect to their substrate specificities. The y4lO gene was mutated in NGR234 (strain NGROmegay4lO) and in NGR Omega nopL, a mutant that does not produce the T3 effector NopL (strain NGR Omega nopLOmegay4lO). When used as inoculants, the symbiotic properties of the mutants differed. Tephrosia vogelii, Phaseolus vulgaris cv. Yudou No. 1, and Vigna unguiculata cv. Sui Qing Dou Jiao formed pink effective nodules with NGR234 and NGR Omega nopL Omega y4lO. Nodules induced by NGR Omega y4lO were first pink but rapidly turned greenish (ineffective nodules), indicating premature senescence. An ultrastructural analysis of the nodules induced by NGR Omega y4lO revealed abnormal formation of enlarged infection droplets in ineffective nodules, whereas symbiosomes harboring a single bacteroid were frequently observed in effective nodules induced by NGR234 or NGR Omega nopL Omega y4lO. It is concluded that Y4lO is a symbiotic determinant involved in the differentiation of symbiosomes. Y4lO mitigated senescence-inducing effects caused by the T3 effector NopL, suggesting synergistic effects for Y4lO and NopL in nitrogen-fixing nodules.
 ...
PMID:Y4lO of Rhizobium sp. strain NGR234 is a symbiotic determinant required for symbiosome differentiation. 2629 32


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>