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)

Post-translational modifications of proteins have critical roles in many cellular processes because they can cause rapid changes in the functions of preexisting proteins, multiprotein complexes and subcellular structures. Sumoylation, a ubiquitin-like dynamic and reversible post-translational modification system, is an enzymatic cascade leading to the covalent attachment of SUMO to it target proteins. This modification involves three steps and different enzymes: SUMO-activating enzyme E1 (SAE1/SAE2), SUMO-conjugating enzyme E2 (UBC9), SUMO ligases E3s, and SUMO cleaving enzymes. Although the identification of SUMO-modified substrates has progressed rapidly, the biological function of SUMO and regulation of SUMO conjugation are still not well understood. Some viral proteins have been identified as substrates for SUMO modification as well as altering the sumoylation status of host cell proteins. We have been studying an unusual adenoviral protein, Gam1, a strong and global transcriptional activator of both viral and cellular genes that inactivates HDAC1. We have recently expanded the known functions of Gam1 by demonstrating that Gam1 also inhibits the SUMO pathway by interfering with the activity of E1 heterodimer (SAE1/SAE2), leading to the accumulation of SUMO-unmodified substrates. Our data provides a clear example of the effects of a viral infection on host sumoylation and supports the idea that viruses have multifunctional protein that can target essential biochemical pathways.
 ...
PMID:Gam1 and the SUMO pathway. 1587 61

The ETS-domain transcription factor Elk-1 is a MAP kinase-inducible transcriptional activator protein. However, in the basal state, its activity is repressed by SUMO-dependent histone deacetylase (HDAC) recruitment. Relief of this repression accompanies the activation process. Here, we demonstrate that PIASx(alpha) acts to facilitate this derepression process. Members of the PIAS family of proteins can act as E3 enzymes that enhance the sumoylation status of a variety of substrates. However, PIASx-mediated coactivation of Elk-1 occurs in an E3 activity-independent manner. PIASx(alpha) binds to Elk-1 in vivo and enhances its transcriptional activity. The coactivating properties of PIASx(alpha) require Elk-1 to be modified with SUMO and the integrity of the SUMO binding motif in PIASx(alpha). PIASx(alpha) activates Elk-1 through alterations in the HAT/HDAC activities associated with Elk-1. In particular, PIASx(alpha) facilitates the loss of the repressive HDAC-2 from sumoylated Elk-1, a key event in the activation of Elk-1 in response to signalling through the ERK MAP kinase pathway. Our data therefore reveal a novel coactivator function for PIASx(alpha) through reversing SUMO-mediated repression of transcription factor activity.
 ...
PMID:PIASx acts as an Elk-1 coactivator by facilitating derepression. 1592 Apr 81

MOT1 encodes an essential ATPase that functions as a general transcriptional regulator in vivo by modulating TATA-binding protein (TBP) DNA-binding activity. Although MOT1 was originally identified both biochemically and in several genetic screens as a transcriptional repressor, a combination of subsequent genetic, chromatin immunoprecipitation, and microarray analysis suggested that MOT1 might also have an additional role in vivo as a transcriptional activator. To better understand the role(s) of MOT1 in vivo, we selected for genomic suppressors of a mot1 temperature-sensitive mutation. This selection identified mutations in SPT15 (TBP) and BUR6, both of which are clearly linked with MOT1 at the functional level. The vast majority of the suppressor mutations, however, unexpectedly occurred in six genes that encode known components of the SUMO pathway and in two other genes with unknown functions, SLX5 and SLX8. Additional results presented here, including extensive synthetic lethality observed between slx5delta and slx8delta and SUMO pathway mutations, suggest that SLX5 and SLX8 are new components or regulators of the SUMO pathway and that SUMO modification might have a general role in transcriptional regulation as part of the TBP regulatory network.
 ...
PMID:Genetic analysis connects SLX5 and SLX8 to the SUMO pathway in Saccharomyces cerevisiae. 1638 68

Sp1 is a ubiquitously expressed transcription factor that binds GC-rich cis elements. Many posttranslational modifications have been implicated in the regulation of Sp1 activity. We now provide evidence for a novel mechanism of Sp1 regulation involving the small ubiquitin-like modifier (SUMO-1). Western blot analysis revealed a high molecular mass Sp1 of 125 kDa that is stabilized by a selective SUMO hydrolase inhibitor and destabilized by a specific SUMO-1 hydrolase. The covalent modification of Sp1 by endogenous SUMO-1 and SUMO-1 that has been fused to green fluorescent protein was demonstrated using transient transfection assays. A high probability sumoylation consensus motif, VK(16)IE(18), is located within the N-terminal negative regulatory domain of Sp1. Either arginine substitution for lysine 16 (Sp1(K16R)) or alanine substitution for glutamic acid 18 (Sp1(E18A)), abrogated Sp1 sumoylation. In vitro SUMO-1 covalently bound affinity-purified GST-Sp1, but not GST-Sp1(K16R). In vivo Sp1 was determined to be N-terminally cleaved, while Sp1(K16R) could not be cleaved indicating that sumoylation and cleavage are coupled through the key regulatory lysine 16. This coupling was evident by the demonstration of an inverse relationship between cellular SUMO-modified Sp1 and N-terminally cleaved Sp1. Compared with Sp1, sumoylation-deficient Sp1(E18A) exhibited enhanced cleavage and was a better transcriptional activator, while constitutively SUMO-1-modified Sp1 was deficient in proteolytic processing and repressed Sp1 transcriptional activity. The repressive effect of sumoylation on Sp1 activity is emphasized through the use of a GAL4 based transactivation assay. A model is proposed defining a mechanism by which sumoylation preserves the integrity of a negative regulatory domain thereby allowing for the inhibition of Sp-dependent transcription.
 ...
PMID:Sumoylation inhibits cleavage of Sp1 N-terminal negative regulatory domain and inhibits Sp1-dependent transcription. 1640 61

Interferon regulatory factor-1 (IRF-1) is an interferon-induced transcriptional activator that suppresses tumors by impeding cell proliferation. Recently, we demonstrated that the level of SUMOylated IRF-1 is elevated in tumor cells, and that SUMOylation of IRF-1 attenuates its tumor-suppressive function. Here we report that SUMOylated IRF-1 mimics IRF-2, an antagonistic repressor, and shows oncogenic potential. To demonstrate the role of SUMOylated IRF-1 in tumorigenesis, we used SUMO-IRF-1 recombinant protein. Stable expression of SUMO-IRF-1 in NIH3T3 cells resulted in focus formation and anchorage-independent growth in soft agar. Inoculation of SUMO-IRF-1-transfected cells into athymic nude mice resulted in tumor formation and infiltration of adipose tissues. Finally, we demonstrated that SUMO-IRF-1 transforms NIH3T3 cells in a dose-dependent manner suggesting that SUMOylated IRF-1 may act as an oncogenic protein in tumor cells.
 ...
PMID:SUMOylated IRF-1 shows oncogenic potential by mimicking IRF-2. 1996 64

The modification of proteins with SUMO (small ubiquitin-related modifier) plays an important role in determining their functional properties. Importantly though, SUMOylation is a highly dynamic process enabling transient responses to be elicited. This dynamism is controlled by two competing conjugating and deconjugating activities. The latter activity is mediated by the SENP [SUMO1/sentrin/SMT3 (suppressor of mif two 3 homologue 1)-specific peptidase] family of SUMO-specific proteases. The transcription factor Elk-1 [ETS (E twenty-six)-like 1] undergoes rapid de-SUMOylation following cellular stimulation with growth factors, and this contributes to its conversion from a SUMO-dependent repressor into a potent transcriptional activator. In the present study we demonstrate an important role for SENP1 in the de-SUMOylation of Elk-1, and therefore an integral role in determining the Elk-1-dependent transcriptional programme. Among the SENPs, Elk-1 preferentially forms a complex with SENP1. This preferential binding is reflected by the higher efficiency of SENP1 in promoting Elk-1 transactivation. Moreover, depletion of SENP1 causes a reciprocal effect and reduces the transactivation properties of Elk-1. Partial redundancy of function with SENP2 is revealed by combinatorial knockdown studies. Importantly, depletion of SENP1 also reduces the activation of the Elk-1 target gene c-FOS. Taken together, these results therefore reveal an important role for SENP1 in the regulation of Elk-1-mediated gene expression in response to mitogenic signalling cues.
 ...
PMID:SENP1 participates in the dynamic regulation of Elk-1 SUMOylation. 2033 93

Mating phenotype in the yeast Saccharomyces cerevisiae is a dynamic trait, and efficient transitions between alternate haploid cell types allow the organism to access the advantageous diploid form. Mating identity is determined by cell type-specific transcriptional regulators, but these factors must be rapidly removed upon mating-type switching to allow the master regulators of the alternate state to establish a new gene expression program. Targeted proteolysis by the ubiquitin-proteasome system is a commonly employed strategy to quickly disassemble regulatory networks, and yeast use this approach to evoke efficient switching from the alpha to the a phenotype by ensuring the rapid removal of the alpha2 transcriptional repressor. Transition to the a cell phenotype, however, also requires the inactivation of the alpha1 transcriptional activator, but the mechanism by which this occurs is currently unknown. Here, we report a central role for the ubiquitin-proteasome system in alpha1 inactivation. The alpha1 protein is constitutively short lived and targeted for rapid turnover by multiple ubiquitin-conjugation pathways. Intriguingly, the alpha-domain, a conserved region of unknown function, acts as a degradation signal for a pathway defined by the SUMO-targeted ligase Slx5-Slx8, which has also been implicated in the rapid destruction of alpha2. Our observations suggest coordinate regulation in the turnover of two master regulatory transcription factors ensures a rapid mating-type switch.
 ...
PMID:Degradation of the Saccharomyces cerevisiae mating-type regulator alpha1: genetic dissection of cis-determinants and trans-acting pathways. 2035 Dec 17

Hypoxia plays a major role in the induction of angiogenesis during tumor development. One mechanism by which tumor cells respond to a reduced oxygen level is via the activation of hypoxia-inducible factor-1 (HIF-1). HIF-1 is an oxygen-dependent transcriptional activator that plays crucial roles in the angiogenesis of tumors and mammalian development. HIF-1 consists of a constitutively expressed HIF-1beta subunit and the highly regulated HIF-1alpha subunits. The stability and activity of HIF-1alpha are regulated by various post-translational modifications, hydroxylation, acetylation, phosphorylation and sumoyaltion. Therefore, HIF-1alpha interacts with several protein factors including PHD, pVHL, ARD-1, SUMO and p300/CBP. Under normoxia, the HIF-1alpha subunit is rapidly degraded via the von Hippel-Lindau tumor suppressor gene product (pVHL)-mediated ubiquitin/proteasome pathway. The association of pVHL and HIF-1alpha under normoxic conditions is triggered by the hydroxylation of prolines and the acetylation of lysine within a polypeptide segment known as the oxygen-dependent degradation (ODD) domain. On the contrary, under the hypoxia condition, the HIF-1alpha subunit becomes stable and interacts with coactivators such as p300/CBP to modulate its transcriptional activity. Under hypoxic conditions, HIF-1 eventually acts as a master regulator of numerous hypoxia-inducible genes. The target genes of HIF-1 are especially related to angiogenesis, cell proliferation and survival, and to glucose and iron metabolism. Moreover, it was reported that the activation of HIF-1alpha is closely associated with a variety of tumors and oncogenic pathways. Hence, the blocking of HIF-1alpha itself or the blocking of HIF-1alpha interacting proteins inhibits tumor growth. Based on these findings, HIF-1 can be a prime target for anticancer therapies. Therefore, this review summarizes the molecular mechanism of HIF-1alpha stability, the biological functions of HIF-1 and its potential applications for cancer therapies.
 ...
PMID:HIF-1alpha: a valid therapeutic target for tumor therapy. 2036 27

Bicoid (Bcd) is a Drosophila morphogenetic protein and a transcriptional activator. Genetic studies have suggested a role of sumoylation in Bcd function, but it is unknown how Bcd activity is affected specifically by its own sumoylation status. Here we show that Bcd is sumoylated in Drosophila cells. We identify a lysine residue of Bcd as the primary sumoylation site. Using a Bcd mutant defective in being sumoylated, we show that sumoylation of Bcd is inhibitory to its ability to activate transcription. We provide evidence suggesting that the SUMO moiety has an intrinsic inhibitory activity for the activator function of Bcd.
 ...
PMID:Drosophila Bicoid is a substrate of sumoylation and its activator function is subject to inhibition by this post-translational modification. 2258 54

Epithelial-mesenchymal transition (EMT) has an essential role in organogenesis and contributes to a host of pathologies, including carcinogenesis. Hypoxia (low oxygen supply) aids tumor metastasis in part by promoting EMT in cancer cells. The underlying mechanism whereby hypoxia orchestrates EMT remains poorly defined. Here we report that SIRT1, a multifaceted player in tumorigenesis, opposed ovarian cancer metastasis in vitro and in vivo by impeding EMT. Hypoxic stress downregulated the expression of SIRT1, primarily at the transcriptional level, by reducing the occupancy of the transcriptional activator Sp1 on the proximal promoter of the SIRT1 gene in a SUMOylation-dependent manner. Further analysis revealed that the SUMO E3 ligase PIASy (also known as PIAS4) was induced by hypoxia and prevented Sp1 from binding to the SIRT1 promoter. Conversely, knockdown of PIASy by small interfering RNA (siRNA) restored Sp1 binding and SIRT1 expression in cancer cells challenged with hypobaric hypoxia, reversed cancer cell EMT, and attenuated metastasis in vivo in nude mice. Importantly, analysis of human ovarian tumor specimens indicated that PIASy expression was positively, whereas SIRT1 expression was inversely, correlated with cancer aggressiveness. In summary, our work has identified a new pathway that links downregulation of SIRT1 to hypoxia-induced EMT in ovarian cancer cells and, as such, sheds light on the development of novel anti-tumor therapeutics.
...
PMID:PIASy mediates hypoxia-induced SIRT1 transcriptional repression and epithelial-to-mesenchymal transition in ovarian cancer cells. 2384 7


1 2 Next >>