scholarly journals E6-associated protein (E6-AP) is a dual function coactivator of steroid hormone receptors

2008 ◽  
Vol 6 (1) ◽  
pp. nrs.06006 ◽  
Author(s):  
Sivapriya Ramamoorthy ◽  
Zafar Nawaz
Keyword(s):  
Hormone Receptors ◽  
Target Genes ◽  
Steroid Hormone ◽  
Enzymatic Activities ◽  
Steroid Hormone Receptors ◽  
Dual Function ◽  
Biological Functions ◽  
Ubiquitin Proteasome Pathway ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway

Steroid hormone receptors (SHR) belong to a large family of ligand-activated transcription factors that perform their biological functions by enhancing the transcription of specific target genes. The transactivation functions of SHRs are regulated by a specialized group of proteins called coactivators. The SHR coactivators represent a growing class of proteins with various enzymatic activities that serve to modify the chromatin to facilitate the transcription of SHR target genes. The ubiquitin-proteasome pathway enzymes have also been added to the growing list of enzymatic activities that are recruited to the SHR target gene promoters during transcription. One such ubiquitin-proteasome pathway enzyme to be identified and characterized as a SHR coactivator was E6-associated protein (E6-AP). E6-AP is a hect (homologous to E6-associated protein carboxy-terminal domain) domain containing E3 ubiquitin ligase that possesses two independent separable functions; a coactivation function and an ubiquitin-protein ligase activity. Being a component of the ubiquitin-proteasome pathway, it is postulated that E6-AP may orchestrate the dynamics of steroid hormone receptor-mediated transcription by regulating the degradation of the transcriptional complexes. E6-AP has also been shown to be involved in the regulation of various aspects of reproduction such as prostate and mammary gland development. Furthermore, it has been demonstrated that E6-AP expression is down-regulated in breast and prostate tumors and that the expression of E6-AP is inversely associated with that of estrogen and androgen receptors. This review summarizes our current knowledge about the structures, molecular mechanisms, spatiotemporal expression patterns and biological functions of E6-AP.

scholarly journals Ligand-dependent Degradation of Smad3 by a Ubiquitin Ligase Complex of ROC1 and Associated Proteins

2001 ◽  
Vol 12 (5) ◽  
pp. 1431-1443 ◽  
Author(s):  
Minoru Fukuchi ◽  
Takeshi Imamura ◽  
Tomoki Chiba ◽  
Takanori Ebisawa ◽  
Masahiro Kawabata ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Target Genes ◽  
Transforming Growth Factor ◽  
Ring Finger ◽  
Transforming Growth Factor Β ◽  
Dependent Manner ◽  
Ubiquitin Proteasome Pathway ◽  
Ubiquitin Ligase Complex ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway

Smads are signal mediators for the members of the transforming growth factor-β (TGF-β) superfamily. Upon phosphorylation by the TGF-β receptors, Smad3 translocates into the nucleus, recruits transcriptional coactivators and corepressors, and regulates transcription of target genes. Here, we show that Smad3 activated by TGF-β is degraded by the ubiquitin–proteasome pathway. Smad3 interacts with a RING finger protein, ROC1, through its C-terminal MH2 domain in a ligand-dependent manner. An E3 ubiquitin ligase complex ROC1-SCFFbw1a consisting of ROC1, Skp1, Cullin1, and Fbw1a (also termed βTrCP1) induces ubiquitination of Smad3. Recruitment of a transcriptional coactivator, p300, to nuclear Smad3 facilitates the interaction with the E3 ligase complex and triggers the degradation process of Smad3. Smad3 bound to ROC1-SCFFbw1a is then exported from the nucleus to the cytoplasm for proteasomal degradation. TGF-β/Smad3 signaling is thus irreversibly terminated by the ubiquitin–proteasome pathway.

PML Protects HIPK2 and p300 from SCF-Mediated Ubiquitin-Dependent Degradation To Activate Transcription.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2653-2653
Author(s):  
Yutaka Shima ◽  
Takito Shima ◽  
Tomoki Chiba ◽  
Tatsuro Irimura ◽  
Issay Kitabayashi
Keyword(s):  
Transcriptional Activation ◽  
Target Genes ◽  
Critical Role ◽  
Nuclear Bodies ◽  
Scf Complex ◽  
Ubiquitin Proteasome Pathway ◽  
Pml Nuclear Bodies ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway

Abstract The Pml gene is the target of t(15;17) chromosome translocation in acute promyelocytic leukemia. PML protein is known to localize in discrete nuclear speckles, named PML nuclear bodies (NBs). In NBs, PML interacts with several transcription factors, such as p53 and AML1, and their co-activators, such as HIPK2 and p300. PML activates transcription of their target genes. PML is thought to stabilize transcription factor complex and function as a mediator in transcription activation, but little is known about the molecular mechanism by which PML activates transcription. To clarify the role of PML in transcription regulation, we purified the PML complex and identified a novel F-box protein (FBP), Skp1, and Cullin1 (Cul1) in the PML complex by LC/MS/MS analysis. FBPs form SCF ubiquitin ligase complexes with Skp1, Cul1 and ROC1 and mediate recognition of specific substrates for ubiquitination. We found that the FBP that we identified here also forms a SCF complex with Skp1, Cul1 and ROC1. To identify substrates for the SCF complex, we tested several proteins that could bind to PML, and found that the FBP promotes degradation of HIPK2 and p300. These degradations were inhibited in the presence of a proteasome inhibitor, MG132. The FBP stimulated ubiquitination of HIPK2. These results suggest that the SCF promotes degradation of these proteins by the ubiquitin-proteasome pathway. The fact that the SCF is a part of the PML complex suggests that PML plays a role in the SCF-mediated degradation of HIPK2 and p300 by the ubiquitin-proteasome pathway. In order to clarify the role of PML in degradation of HIPK2 and p300, we tested effects of PML on the degradation and found that PML inhibited the SCF-mediated degradation of HIPK2 and p300 without inhibition of ubiquitination. To clarify roles of HIPK2, PML IV and the FBP in p53-dependent transcription, we performed reporter analysis using the MDM2 promoter in H1299 cells. Since the FBP promotes degradation of HIPK2, we initially thought that the FBP might inhibit activation of p53-dependent transcription by HIPK2 and PML IV. However, the FBP, HIPK2 and PML synergistically stimulated the p53-dependent transcriptional activation. Taken together our data suggest that the SCF-induced ubiquitination of transcription co-activators HIPK2 and p300 plays a critical role in transcriptional regulation, and that PML stimulates transcription by protecting HIPK2 and p300 from ubiquitin-dependent degradation.

The androgen receptor DNA-binding domain determines androgen selectivity of transcriptional response

2006 ◽  
Vol 34 (6) ◽  
pp. 1089-1094 ◽  
Author(s):  
G. Verrijdt ◽  
T. Tanner ◽  
U. Moehren ◽  
L. Callewaert ◽  
A. Haelens ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Dna Binding ◽  
Cellular Response ◽  
Hormone Receptors ◽  
Target Genes ◽  
Steroid Hormone ◽  
Prostate Gland ◽  
Steroid Hormone Receptors ◽  
Binding Motif

The AR (androgen receptor) is a hormone-dependent transcription factor that translates circulating androgen hormone levels into a physiological cellular response by directly regulating the expression of its target genes. It is the key molecule in e.g. the development and maintenance of the male sexual characteristics, spermatocyte production and prostate gland development and growth. It is also a major factor in the onset and maintenance of prostate cancer and a first target for pharmaceutical action against the further proliferation of prostate cancer cells. The AR is a member of the steroid hormone receptors, a group of steroid-inducible transcription factors sharing an identical consensus DNA-binding motif. The problem of how specificity in gene activation is achieved among the different members of this nuclear receptor subfamily is still unclear. In this report, we describe our investigations on how the AR can specifically activate its target genes, while the other steroid hormone receptors do not, despite having the same consensus monomeric DNA-binding motif. In this respect, we describe how the AR interacts with a newly identified class of steroid-response elements to which only the AR and not, for example, the glucocorticoid receptor can bind.

scholarly journals Isolation of Hsp90 mutants by screening for decreased steroid receptor function

1993 ◽  
Vol 90 (23) ◽  
pp. 11424-11428 ◽  
Author(s):  
S P Bohen ◽  
K R Yamamoto
Keyword(s):  
Heat Shock ◽  
Glucocorticoid Receptor ◽  
Hormone Receptors ◽  
Steroid Hormone ◽  
Steroid Hormone Receptors ◽  
Cellular Proteins ◽  
Receptor Function ◽  
Biological Functions ◽  
High Affinity ◽  
Shock Proteins

The 90-kDa heat shock protein Hsp90 represents a highly conserved strongly expressed gene family; in Saccharomyces cerevisiae, Hsp90 proteins are essential for cell viability. Hsp90 interacts with certain cellular proteins, including steroid hormone receptors, tyrosine and serine/threonine kinases, and other heat shock proteins, but its biological functions are not understood. The unliganded glucocorticoid receptor must interact with Hsp90 to acquire competence for high-affinity hormone binding and subsequent transcriptional regulation. By screening in yeast for defects in glucocorticoid receptor function, Hsp90 mutants were isolated. Four such mutants are described, all of which interact with the glucocorticoid receptor but display distinct defects in ligand responsiveness and differences in growth and resistance to high temperature.

scholarly journals Urban Renewal in the Nucleus: Is Protein Turnover by Proteasomes Absolutely Required for Nuclear Receptor-Regulated Transcription?

2004 ◽  
Vol 18 (3) ◽  
pp. 493-499 ◽  
Author(s):  
Zafar Nawaz ◽  
Bert W. O’Malley
Keyword(s):  
Protein Degradation ◽  
Nuclear Receptors ◽  
Nuclear Receptor ◽  
Gene Transcription ◽  
Hormone Receptor ◽  
Target Genes ◽  
Nuclear Hormone Receptor ◽  
Ubiquitin Proteasome Pathway ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway

Abstract The importance of the ubiquitin proteasome pathway in higher eukaryotes has been well established in cell cycle regulation, signal transduction, and cell differentiation, but has only recently been linked to nuclear hormone receptor-regulated gene transcription. Characterization of a number of ubiquitin proteasome pathway enzymes as coactivators and observations that several nuclear receptors are ubiquitinated and degraded in the course of their nuclear activities provide evidence that ubiquitin proteasome-mediated protein degradation plays an integral role in eukaryotic transcription. In addition to receptors, studies have revealed that coactivators are ubiquitinated and degraded via the proteasome. The notion that the ubiquitin proteasome pathway is involved in gene transcription is further strengthened by the fact that ubiquitin proteasome pathway enzymes are recruited to the promoters of target genes and that proteasome-dependent degradation of nuclear receptors is required for efficient transcriptional activity. These findings suggest that protein degradation is coupled with nuclear receptor coactivation activity. It is possible that the ubiquitin proteasome pathway modulates transcription by promoting remodeling and turnover of the nuclear receptor-transcription complex. In this review, we discus the possible role of the ubiquitin proteasome pathway in nuclear hormone receptor-regulated gene transcription.

scholarly journals Steroid hormone receptors and dietary ligands: a selected review

2002 ◽  
Vol 61 (1) ◽  
pp. 105-122 ◽  
Author(s):  
Miriam N. Jacobs* ◽  
David F. V. Lewis
Keyword(s):  
Hormone Receptors ◽  
Target Genes ◽  
Steroid Hormone ◽  
Pregnane X Receptor ◽  
Steroid Hormone Receptors ◽  
Receptor Interaction ◽  
Peroxisome Proliferator ◽  
Dietary Intakes ◽  
Food Contaminants ◽  
Exogenous Compounds

Members of the nuclear steroid hormone superfamily mediate essential physiological functions. Steroid hormone receptors (SHR) act directly on DNA, regulate the synthesis of their target genes and are usually activated by ligand binding. Both endogenous and exogenous compounds and their metabolites may act as activators of SHR and disruptors of endocrine, cellular and lipid homeostasis. The endogenous ligands are generally steroids such as 17β-oestradiol, androgens, progesterone and pregnenolone. The exogenous compounds are usually delivered through the diet and include non-steroidal ligands. Examples of such ligands include isoflavanoids or phyto-oestrogens, and food contaminants such as exogenous oestrogens from hormone-treated cattle, pesticides, polychlorinated biphenyls and plasticisers. Certain drugs are also ligands; so nuclear receptors are also important drug targets for intervention in disease processes. The present review summarises recent reports on ligand-activated SHR that describe the selective regulation of a tightly-controlled cross-talking network involving exchange of ligands, and the control of major classes of cytochrome P450 (CYP) isoforms which metabolise many bioactive exogenous compounds. Many CYP have broad substrate activity and appear to be integrated into a coordinated metabolic pathway, such that whilst some receptors are ligand specific, other sensors may have a broader specificity and low ligand affinity to monitor aggregate levels of inducers. They can then trigger production of metabolising enzymes to defend against possible toxic nutrients and xenobiotic compounds. The influence of dietary intakes of nutrients and non-nutrients on the human oestrogen receptors (α and β), the aryl hydrocarbon receptor, the pregnane X receptor, the constitutive androstane receptor, and the peroxisome proliferator-activated receptors (α and γ), can be examined by utilising computer-generated molecular models of the ligand–receptor interaction, based on information generated from crystallographic data and sequence homology. In relation to experimental and observed data, molecular modelling can provide a scientifically sound perspective on the potential risk and benefits to human health from dietary exposure to hormone-mimicking chemicals, providing a useful tool in drug development and in a situation of considerable public concern.

scholarly journals Distribution and interrelationship of ubiquitin proteasome pathway component activities and ubiquitin pools in various porcine tissues

2007 ◽  
pp. 341-350 ◽  
Author(s):  
MB Patel ◽  
M Majetschak
Keyword(s):  
Skeletal Muscle ◽  
Biological Functions ◽  
Ubiquitin Protein Ligase ◽  
Ubiquitin Proteasome Pathway ◽  
Protein Ligation ◽  
Tissue Levels ◽  
Linear Relationships ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway ◽  
Porcine Tissues

The ubiquitin-proteasome pathway fulfills major biological functions, but its physiologic tissue distribution and the interrelationship between pathway component activities and ubiquitin pools are unknown. Therefore, we analyzed free and conjugated ubiquitin, ubiquitin-protein ligation rates (UbPL) and chymotryptic- and tryptic-like proteasome peptidase activities in porcine skeletal muscle, heart, lung, liver, spleen and kidney (n=5 each). There were considerable differences between tissues (p<0.05 for all parameters). Lung and spleen showed high levels of free and conjugated ubiquitin and high UbPL. Proteasome activities were highest in kidney and heart. There were linear relationships between tryptic-like and chymotryptic-like proteasome peptidase activities (r(2) = 0.624, p<0.001) and between free and conjugated ubiquitin tissue levels (r(2) = 0.623, p<0.001). Tissue levels of free and conjugated ubiquitin correlated linear with UbPL (p<0.005), but they were not correlated with proteasome peptidase activities. The results suggest that tissue ubiquitin pools are tightly regulated and indicate a constant proportion of conjugated ubiquitin. They further support the hypothesis that ubiquitin-protein ligase systems, and probably deubiquitylating enzymes, are key regulators of ubiquitin homeostasis. The detected differences are suggestive of tissue-specific roles of ubiquitin-proteasome pathway components. Besides the known importance of the ubiquitin proteasome pathway in heart, kidney and the immune system, the results suggest the lung as another organ in which ubiquitin proteasome pathway components may also significantly contribute to disease processes.

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