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Biomedical subjects

Edward T H Yeh

Publications and source records attributed to Edward T H Yeh.

At least 19 recordsLinked to original sources
PubMed2006

Neddylation of a breast cancer-associated protein recruits a class III histone deacetylase that represses NFkappaB-dependent transcription.

Neddylation has an important role in ubiquitin-mediated protein degradation through modification of cullins, which are the main substrates for NEDD8 modification. Here, we show that breast cancer-associated protein 3 (BCA3) is a NEDD8 substrate. BCA3 suppressed NFkappaB-dependent transcription through its ability to bind to p65 and the cyclin D1 promoter in a neddylation-dependent manner. Transcriptional suppression mediated by BCA3 may be attributed to the ability of neddylated BCA3 to recruit SIRT1, a class III histone deacetylase. Silencing of endogenous BCA3 in DU145 and MCF7 cells enhanced NFkappaB transcription and inhibited tumour necrosis factor (TNF)alpha-induced apoptosis. Conversely, BCA3 silencing could be reversed by over-expression of wild-type BCA3 and SENP8, a NEDD8-specific protease, but not by neddylation-deficient BCA3 or a SENP8 mutant. These results provide a crucial link between neddylation and transcriptional regulation by SIRT1, a NAD-dependent histone deacetylase that prolongs life span in yeast and worms.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Characterization of a family of nucleolar SUMO-specific proteases with preference for SUMO-2 or SUMO-3.

SUMOylation is a reversible process regulated by a family of sentrin/SUMO-specific proteases (SENPs). Of the six SENP family members, except for SENP1 and SENP2, the substrate specificities of the rest of SENPs are not well defined. Here, we have described SENP5, which has restricted substrate specificity. SENP5 showed SUMO-3 C-terminal hydrolase activity but could not process pro-SUMO-1 in vitro. Furthermore, SENP5 showed more limited isopeptidase activity in vitro. In vivo, SENP5 showed isopeptidase activity against SUMO-2 and SUMO-3 conjugates but not against SUMO-1 conjugates. Native SENP5 localized mainly to the nucleolus but was also found in the nucleus. The N terminus of SENP5 contains a stretch of amino acids responsible for the nucleolar localization of SENP5. N-terminal-truncated SENP5 co-localized with PML, a known SUMO substrate. Using PML SUMOylation mutants as model substrates, we showed that SENP5 can remove poly-SUMO-2 or poly-SUMO-3 from the Lys160 or Lys490 positions of PML. However, SENP5 could not remove SUMO-1 from the Lys160 or Lys490 positions of PML. Nonetheless, SENP5 could remove SUMO-1, -2, and -3 from the Lys65 position of PML. Thus, SENP5 also possesses limited SUMO-1 isopeptidase activity. We were also able to show that SENP3 has substrate specificity similar to that of SENP5. Thus, SENP3 and SENP5 constitute a subfamily of SENPs that regulate the formation of SUMO-2 or SUMO-3 conjugates and, to a less extent, SUMO-1 modification.

Animals↗
PubMed2006

A novel approach to studying transformation of human stem cells into cardiac cells in vivo.

Stem cell transplantation has been proposed as a novel means of regenerating new myocardium following cardiac damage. Many laboratories have demonstrated that stem cells from different sources have the potential to transform into cardiomyocytes. Human peripheral blood CD34+ cells were transplanted into the hearts of mice with severe combined immune deficiency syndrome, and it was demonstrated that human stem cells could transform into cardiomyocytes, endothelial cells and smooth muscle cells. Using single cell preparation, cell sorting and fluorescent in situ hybridization, human peripheral blood CD34+ cells were transformed into cardiomyocytes mainly through cell fusion, whereas endothelial cells were derived through direct differentiation of the transplanted stem cells. This analytical method should provide a novel approach to identifying the mechanisms of stem cell transformation into cardiomyocytes in vivo.

Animals↗
PubMed2006

Nucleocytoplasmic shuttling modulates activity and ubiquitination-dependent turnover of SUMO-specific protease 2.

Small ubiquitin-related modifier (SUMO) proteins are conjugated to numerous polypeptides in cells, and attachment of SUMO plays important roles in regulating the activity, stability, and subcellular localization of modified proteins. SUMO modification of proteins is a dynamic and reversible process. A family of SUMO-specific proteases catalyzes the deconjugation of SUMO-modified proteins. Members of the Sentrin (also known as SUMO)-specific protease (SENP) family have been characterized with unique subcellular localizations. However, little is known about the functional significance of or the regulatory mechanism derived from the specific localizations of the SENPs. Here we identify a bipartite nuclear localization signal (NLS) and a CRM1-dependent nuclear export signal (NES) in the SUMO protease SENP2. Both the NLS and the NES are located in the nonhomologous domains of SENP2 and are not conserved among other members of the SENP family. Using a series of SENP2 mutants and a heterokaryon assay, we demonstrate that SENP2 shuttles between the nucleus and the cytoplasm and that the shuttling is blocked by mutations in the NES or by treating cells with leptomycin B. We show that SENP2 can be polyubiquitinated in vivo and degraded through proteolysis. Restricting SENP2 in the nucleus by mutations in the NES impairs its polyubiquitination, whereas a cytoplasm-localized SENP2 made by introducing mutations in the NLS can be efficiently polyubiquitinated, suggesting that SENP2 is ubiquitinated in the cytoplasm. Finally, treating cells with MG132 leads to accumulation of polyubiquitinated SENP2, indicating that SENP2 is degraded through the 26S proteolysis pathway. Thus, the function of SENP2 is regulated by both nucleocytoplasmic shuttling and polyubiquitin-mediated degradation.

Active Transport, Cell Nucleus↗
PubMed2006

Cardiotoxicity induced by chemotherapy and antibody therapy.

Modern cancer therapy employs a combination of chemotherapy, antibody-based therapy, radiotherapy, and surgery to prolong life and provide cure. However, many of the chemotherapy agents and antibodies, either singly or in combination, can affect the cardiovascular system. Common cardiovascular manifestations of these therapies include heart failure, ischemia, hypotension, hypertension, edema, QT prolongation, bradyarrhythmia, and thromboembolism. The patient's age, underlying cardiovascular status, and genetic background, as well as the route of drug administration and dosage, can all contribute to the development of cardiotoxicity. Strategies to monitor for and to manage these effects are discussed in this review.

Antibodies, Neoplasm↗
PubMed2006

Role of desumoylation in the development of prostate cancer.

SUMO is a novel ubiquitin-like protein that can covalently modify a large number of nuclear proteins. SUMO modification has emerged as an important regulatory mechanism for protein function and localization. Sumoylation is a dynamic process that is mediated by activating (E1), conjugating (E2), and ligating (E3) enzymes and is readily reversed by a family of SUMO-specific proteases (SENPs). Since SUMO was discovered 10 years ago, the biologic contribution of this posttranslational modification has remained unclear. In this review, we report that SENP1, a member of the SENP family, is overexpressed in human prostate cancer specimens. The induction of SENP1 is observed with the chronic exposure of prostate cancer cells to androgen and/or interleukin (IL) 6. SENP1 upregulation modulates the transcriptional activity of androgen receptors (ARs) and c-Jun, as well as cyclin D1 expression. Initial in vivo data from transgenic mice indicate that overexpression of SENP1 in the prostate leads to the development of prostatic intraepithelial neoplasia at an early age. Collectively, these studies indicate that overexpression of SENP1 is associated with prostate cancer development.

Animals↗
PubMed2005

A proline-90 residue unique to SUMO-4 prevents maturation and sumoylation.

Four small ubiquitin-related modifier (SUMO) genes have been identified in humans. However, little is known about the basic biology of SUMO-4. Here, we report that SUMO-4 differs from SUMO-1, -2, and -3 in that the maturation process of SUMO-4 to active form containing C-terminal di-glycine residues is inhibited by a unique proline residue located at position 90 (Pro-90). Although, both the hydrolase and isopeptidase activities of SUMO peptidases are significantly diminished by Pro-90 as compared to Gln-90 (glutamine) in mutated SUMO genes, only the defective hydrolase activity appears to be biologically relevant. Native SUMO-4, thus, appears to be unable to form covalent isopeptide bonds with substrates. A biological role of SUMO-4, through non-covalent interactions is proposed.

Base Sequence↗
PubMed2005

Inhibition of tumor-necrosis-factor-alpha induced endothelial cell activation by a new class of PPAR-gamma agonists. An in vitro study showing receptor-independent effects.

Proinflammatory cytokines and adhesion molecules expressed by endothelial cells (ECs) play a critical role in initiating and promoting atherosclerosis. Agents that oppose these inflammatory effects in vascular cells include peroxisome proliferator-activated receptor-gamma (PPAR-gamma) ligands, including 15-deoxy-delta(12,14)-prostaglandin J2 (15d-PGJ2) and synthetic thiazolidinediones. Recently, a new structural class of potent PPAR-gamma agonists, 1,1-bis(3'-indolyl)-1-(p-substituted phenyl) methanes, has been characterized. The purpose of this study was to evaluate the anti-inflammatory effects of two PPAR-gamma-active members of this class, 1,1-bis(3'-indolyl)-1-(p-t-butylphenyl)methane (DIM-C-pPhtBu) and 1,1-bis(3'-indolyl)-1-(p-biphenyl)methane (DIM-C-pPhC(6)H(5)), in ECs in vitro. Pretreatment of ECs with DIM-C-pPhC(6)H(5), DIM-C- pPhtBu, or 15d-PGJ2 decreased tumor necrosis factor-alpha (TNF-alpha)-induced intercellular adhesion molecule (ICAM)-1 expression in a concentration-dependent manner. At a concentration of 10 microM, DIM-C-pPhtBu and DIM-C-pPhC(6)H(5) decreased ICAM-1 expression by 77.5 and 71.3%, respectively, and comparable inhibition (84.4%) was observed for 10 microM 15d-PGJ2 (p < 0.05). In contrast, 10 microM ciglitazone and DIM-C-pPhCH(3), which exhibits low PPAR-gamma agonist activity, were inactive. The two new PPAR-gamma agonists and 15d-PGJ2 also inhibited TNF-alpha-induced interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1) production in supernatants of TNF-alpha-stimulated ECs, whereas ciglitazone and DIM-C-pPhCH(3) did not decrease TNF-alpha-induced expression of these two proteins. This new structural class of PPAR-gamma agonists inhibited the expression of ICAM-1 and the production of IL-6 and MCP-1 in TNF-alpha-activated ECs at lower concentrations than other synthetic PPAR-gamma agonists, suggesting the potential clinical utility of 1,1-bis(3'-indolyl)-1-(p-substituted phenyl) methanes for decreasing endothelial inflammation.

Cells, Cultured↗
PubMed2005

Fusion of the SUMO/Sentrin-specific protease 1 gene SENP1 and the embryonic polarity-related mesoderm development gene MESDC2 in a patient with an infantile teratoma and a constitutional t(12;15)(q13;q25).

Recently, we identified a patient with an infantile sacrococcygeal teratoma and a constitutional t(12;15)(q13;q25). Here, we show that, as a result of this chromosomal translocation, the SUMO/Sentrin-specific protease 1 gene (SENP1) on chromosome 12 and the embryonic polarity-related mesoderm development gene (MESDC2) on chromosome 15 are disrupted and fused. Both reciprocal SENP1-MESDC2 (SEME) and MESDC2-SENP1 (MESE) fusion genes are transcribed in tumor-derived cells and their open reading frames encode aberrant proteins. As a consequence of this, and in contrast to wild-type (WT) MESDC2, the translocation-associated SEME protein is no longer targeted to the endoplasmatic reticulum, leading to a presumed loss-of-function as a chaperone for the WNT co-receptors LRP5 and/or LRP6. Ultimately, this might lead to abnormal development and/or routing of germ cell tumor precursor cells. SUMO, a post-translational modifier, plays an important role in several cellular key processes and is cleaved from its substrates by WT SENP1. Using a PML desumoylation assay, we found that translocation-associated MESE proteins exhibit desumoylation capacities similar to those observed for WT SENP1. We speculate that spatio-temporal disturbances in desumoylating activities during critical stages of embryonic development might have predisposed the patient. Together, the constitutional t(12;15)(q13;q25) translocation revealed two novel candidate genes for neonatal/infantile GCT development: MESDC2 and SENP1.

Animals↗
PubMed2005

Differential regulation of c-Jun-dependent transcription by SUMO-specific proteases.

c-Jun is a transcription factor that plays an important role in regulating cell growth, apoptosis, differentiation, and transformation. The transcriptional activity of c-Jun can be regulated by both phosphorylation and sumoylation. It has also been shown that c-Jun transcription can be regulated by SuPr-1, an alternatively spliced form of SUMO-specific protease 2 (SENP2). However, the ability of SuPr-1 to enhance c-Jun transcription is dependent on promyelocytic leukemia but is independent of the desumoylation activity of SuPr-1. Here, we show that SUMO-specific protease 1 (SENP1) also markedly enhances the transcription activity of c-Jun. The action of SENP1 on c-Jun transcription is independent of the sumoylation and phosphorylation status of c-Jun but is critically dependent on the desumoylation activity of SENP1. We further show that p300 is essential for SENP1 to enhance c-Jun-dependent transcription because SENP1 can desumoylate the CRD1 domain of p300, thereby releasing the cis-repression of CRD1 on p300. Thus, two SUMO-specific proteases regulate c-Jun-dependent transcription through entirely different mechanisms.

Animals↗
PubMed2005

High-sensitivity C-reactive protein as a risk assessment tool for cardiovascular disease.

Almost half of first cardiovascular events occur in individuals with no known risk factors. Attempts in the last decade to predict cardiovascular risk more accurately have led to the emergence of a novel risk factor, C-reactive protein (CRP), which has proved to be as good a risk predictor as low-density lipoprotein cholesterol. C-reactive protein is an index of inflammation that is now believed to promote directly all stages of atherosclerosis, including plaque rupture. As measured by high-sensitivity assays, high-sensitivity CRP (hs-CRP) also independently predicts recurrent events in patients with known coronary artery diseases. Recent evidence implicates hs-CRP, and thus inflammation, in the metabolic syndrome and diabetes mellitus, particularly in women. As a clinical tool for cardiovascular risk assessment, hs-CRP testing enhances information provided by lipid screening or global risk assessment. Statin therapy and other interventions can lower hs-CRP. Whether or not such reductions can prevent cardiovascular events is under investigation.

Biomarkers↗
PubMed2005

The pleiotropic effects of statins.

PURPOSE OF REVIEW: 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are the most widely prescribed drugs worldwide for lowering cholesterol levels. In use for more than 15 years, they have demonstrated efficacy, safety, and tolerability across a broad range of patients. This class of drugs has been designed to lower the cholesterol level by competitively inhibiting the enzyme responsible for its biosynthesis and thereby to play a major role in reducing cardiovascular risk. However, both basic evidence and clinical evidence also supports the idea that reductions in cardiovascular risk are dependent on mechanisms beyond cholesterol reduction alone, such as the reduction of endothelial dysfunction, inhibition of inflammatory responses, stabilization of atherosclerotic plaques, and modulation of procoagulant activity and platelet function. RECENT FINDINGS: In fact, as shown in several clinical trials, the beneficial effects of statin treatment begin earlier than its cholesterol-lowering effect. These other mechanisms could act in concert with the potent low-density lipoprotein cholesterol-lowering effects of this class of drugs to exert early and lasting cardiovascular protective effects. Recently, several studies have shown that an intensive lipid-lowering regimen with a statin provides greater protection against death or major cardiovascular events than does a standard regimen. SUMMARY: This review summarizes the new findings in these pleiotropic effects and describes their impact on vascular processes.

Anticholesteremic Agents↗
PubMed2005

A proatherogenic role for C-reactive protein in vivo.

PURPOSE OF REVIEW: We have selectively reviewed some of the latest papers on the mechanistic role of C-reactive protein in atherosclerotic cardiovascular disease. RECENT DEVELOPMENTS: C-reactive protein is known to activate the classic pathway of the complement system. One paper examined the role of C-reactive protein in complement activation by enzymatically remodeled LDL proteins. Enzymatically remodeled LDL was found to induce complement activation with or without C-reactive protein, but in the presence of C-reactive protein the activation of complement halted before its terminal sequence. Complement activation by C-reactive protein in atherogenesis remains controversial. Different laboratories have reported the multi-organ origin of C-reactive protein. The atherosclerotic lesion itself is another place where C-reactive protein could be produced. Numerous studies have continued to dissect the potential diverse proatherogenic actions of C-reactive protein on cultured vascular cells. Caution must be exercised in inadequately controlled studies that have unwittingly used commercial C-reactive protein preparations contaminated by other bioactive components. In contrast to in-vitro experiments, in-vivo studies that support a proatherogenic role of C-reactive protein are less likely to be subject to misinterpretation. SUMMARY: Evidence suggests that C-reactive protein is a proatherogenic molecule that plays an active role. The amount of C-reactive protein in lesions is determined by its plasma levels and its local production. The biological effect of C-reactive protein on atherosclerosis development seems to encompass a complex network of interactions with other players in immunity and inflammation, such as the complement system, as well as a direct effect of C-reactive protein on the cells involved in lesion growth and development.

Animals↗
PubMed2005

Kaposi's sarcoma-associated herpesvirus K-bZIP represses gene transcription via SUMO modification.

Kaposi's sarcoma-associated herpesvirus (KSHV) is a human gammaherpesvirus implicated in AIDS-related neoplasms. Previously, we demonstrated that the early lytic gene product K-bZIP is a transcriptional repressor that affects a subset of viral gene transcriptions mediated by the viral transactivator K-Rta (Y. Izumiya et al. J. Virol. 77:1441-1451, 2003). Sumoylation has emerged as an important posttranslational modification that affects the location and function of cellular and viral proteins and also plays a significant role in transcriptional repression along with Ubc9, the E2 SUMO conjugation enzyme. Here, we provide evidence that K-bZIP is sumoylated at the lysine 158 residue and associates with Ubc9 both in a cell-free system and in virus-infected BCBL-1 cells. Reporter assays showed that the expression of SUMO-specific protease 1 attenuated the transcriptional repression activity of K-bZIP. The expression of a K-bZIPK158R mutant, which was no longer sumoylated, exhibited the reduced transcriptional repression activity. This indicates that sumoylation plays an important part in the transcriptional repression activity of K-bZIP. Finally, chromatin immunoprecipitation experiments demonstrated that K-bZIP interacts with and recruits Ubc9 to specific KSHV promoters. Thus, our data indicate that K-bZIP is a SUMO adaptor, which recruits Ubc9 to specific viral target promoters, thereby exerting its transcriptional repression activity.

Basic-Leucine Zipper Transcription Factors↗
PubMed2004

Both cell fusion and transdifferentiation account for the transformation of human peripheral blood CD34-positive cells into cardiomyocytes in vivo.

BACKGROUND: Adult human peripheral blood CD34-positive (CD34+) cells appear to transform into cardiomyocytes in the injured hearts of severe combined immunodeficient mice. It remains unclear, however, whether the apparent transformation is the result of transdifferentiation of the donor stem cells or of fusion of the donor cell with the cardiomyocyte of the recipients. METHODS AND RESULTS: We performed flow cytometry analyses of cells isolated from the hearts of mice that received human CD34+ cells. Human HLA-ABC antigen and cardiac troponin T or Nkx2.5 were used as markers for cardiomyocytes derived from human CD34+ cells, and HLA-ABC and VE-cadherin were used to identify the transformed endothelial cells. The double-positive cells were collected and interphase fluorescence in situ hybridization was used to detect the expression of human and mouse X chromosomes in these cells. We found that 73.3% of nuclei derived from HLA+ and troponin T+ or Nkx2.5+ cardiomyocytes contain both human and mouse X chromosomes and 23.7% contain only human X chromosome. In contrast, the nuclei of HLA-, troponin T+ cells contain only mouse X chromosomes. Furthermore, 97.3% of endothelial cells derived from CD34+ cells contained human X chromosome only. CONCLUSIONS: Thus, both cell fusion and transdifferentiation may account for the transformation of peripheral blood CD34+ cells into cardiomyocytes in vivo.

Animals↗