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1.  TAK1 regulates autophagic cell death by suppressing the phosphorylation of p70 S6 kinase 1 
Scientific Reports  2013;3:1561.
There is growing interest in identifying regulators of autophagy. The molecular mechanism underlying transforming growth factor-β activated kinase 1 (TAK1)-induced autophagy is poorly understood. We found that TAK1 inhibits p70 S6 kinase1 (S6K1) phosphorylation by interfering interaction of raptor with S6K1, thus inducing autophagy. The factors that determine whether autophagy is cytoprotective or cytotoxic have not been fully elucidated. In Drosophila, TAK1 overexpression leads to an impaired eye phenotype despite inhibition of apoptosis, indicating that the phenotype was mainly due to autophagy. Also, TAK1 overexpression increases lactate dehydrogenase (LDH) level in mammalian cells. When treated with autophagy inhibitors, the level of TAK1-induced cytotoxicity or cell death was significantly attenuated, indicating that TAK1 induces cytotoxic autophagic cell death. This study provides the first in vitro and in vivo evidence of TAK1-induced autophagy and we believe that our findings significantly contribute to the understanding of the mechanisms underlying the induction of autophagy.
doi:10.1038/srep01561
PMCID: PMC3609023  PMID: 23532117
2.  Crucial Role of TSC-22 in Preventing the Proteasomal Degradation of p53 in Cervical Cancer 
PLoS ONE  2012;7(8):e42006.
The p53 tumor suppressor function can be compromised in many tumors by the cellular antagonist HDM2 and human papillomavirus oncogene E6 that induce p53 degradation. Restoration of p53 activity has strong therapeutic potential. Here, we identified TSC-22 as a novel p53-interacting protein and show its novel function as a positive regulator of p53. We found that TSC-22 level was significantly down-regulated in cervical cancer tissues. Moreover, over-expression of TSC-22 was sufficient to inhibit cell proliferation, promote cellular apoptosis in cervical cancer cells and suppress growth of xenograft tumors in mice. Expression of also TSC-22 enhanced the protein level of p53 by protecting it from poly-ubiquitination. When bound to the motif between amino acids 100 and 200 of p53, TSC-22 inhibited the HDM2- and E6-mediated p53 poly-ubiquitination and degradation. Consequently, ectopic over-expression of TSC-22 activated the function of p53, followed by increased expression of p21Waf1/Cip1 and PUMA in human cervical cancer cell lines. Interestingly, TSC-22 did not affect the interaction between p53 and HDM2. Knock-down of TSC-22 by small interfering RNA clearly enhanced the poly-ubiquitination of p53, leading to the degradation of p53. These results suggest that TSC-22 acts as a tumor suppressor by safeguarding p53 from poly-ubiquitination mediated-degradation.
doi:10.1371/journal.pone.0042006
PMCID: PMC3411576  PMID: 22870275
3.  Differential Expression of Extracellular Matrix Proteins in Senescent and Young Human Fibroblasts: a Comparative Proteomics and Microarray Study 
Molecules and Cells  2011;32(1):99-106.
The extracellular matrix (ECM) provides an essential structural framework for cell attachment, proliferation, and differentiation, and undergoes progressive changes during senescence. To investigate changes in protein expression in the extracellular matrix between young and senescent fibroblasts, we compared proteomic data (LTQ-FT) with cDNA microarray results. The peptide counts from the proteomics analysis were used to evaluate the level of ECM protein expression by young cells and senescent cells, and ECM protein expression data were compared with the microarray data. After completing the comparative analysis, we grouped the genes into four categories. Class I included genes with increased expression levels in both analyses, while class IV contained genes with reduced expression in both analyses. Class II and Class III contained genes with an inconsistent expression pattern. Finally, we validated the comparative analysis results by examining the expression level of the specific gene from each category using Western blot analysis and semiquantitative RT-PCR. Our results demonstrate that comparative analysis can be used to identify differentially expressed genes.
doi:10.1007/s10059-011-0064-0
PMCID: PMC3887658  PMID: 21573704
extracellular matrix; microarray; proteomics
4.  Validation of the 2009 TNM Classification for Renal Cell Carcinoma: Comparison with the 2002 TNM Classification by Concordance Index 
Korean Journal of Urology  2011;52(8):524-530.
Purpose
To assess the validity of the 2009 TNM classification for renal cell carcinoma (RCC) and compare its ability to predict survival relative to the 2002 classification.
Materials and Methods
We identified 1,691 patients who underwent radical nephrectomy or partial nephrectomy for unilateral, sporadic RCC between 1989 and 2007. Cancer-specific survival was estimated by the Kaplan-Meier method and was compared among groups by the log-rank test. Associations of the 2002 and 2009 TNM classifications with death from RCC were evaluated by Cox proportional hazards regression models. The predictive abilities of the two classifications were compared by using Harrell's concordance (c) index.
Results
There were 234 deaths from RCC a mean of 38 months after nephrectomy. According to the 2002 primary tumor classification, 5-year cancer-specific survival was 97.6% in T1a, 92.0% in T1b, 83.3% in T2, 61.9% in T3a, 51.1% in T3b, 40.0% in T3c, and 33.6% in T4 (p for trend<0.001). According to the 2009 classification, 5-year cancer-specific survival was 83.2% in T2a, 83.8% in T2b, 62.6% in T3a, 41.1% in T3b, 50.0% in T3c, and 26.1% in T4 (p for trend<0.001). The c index for the 2002 primary tumor classification was 0.810 in the univariate analysis and increased to 0.906 in the multivariate analysis. The c index for the 2009 primary tumor classification was 0.808 in the univariate analysis and increased to 0.904 in the multivariate analysis.
Conclusions
Our data suggest that the predictive ability the 2009 TNM classification is not superior to that of the 2002 classification.
doi:10.4111/kju.2011.52.8.524
PMCID: PMC3162217  PMID: 21927698
Kidney neoplasms; Mortality; Neoplasm staging; Prognosis; Renal cell carcinoma
5.  Predictive Characteristics of Malignant Pheochromocytoma 
Korean Journal of Urology  2011;52(4):241-246.
Purpose
The prognosis of patients with malignant pheochromocytoma is poor, but the predictive factors are not well understood. We aimed to identify the clinical characteristics predictive of malignancy after initial surgical removal in patients with pheochromocytoma.
Materials and Methods
We retrospectively reviewed the records of 152 patients diagnosed with pheochromocytoma, including 5 (3.3%) with metastasis at the time of the initial surgical excision and 12 (7.9%) who developed metastasis during follow-up. To determine the factors predictive of malignancy, we compared clinical, radiographical, and urinary chemical findings between patients with benign and malignant disease. Mean follow-up was 41.5 months (range, 0.9-298 months) after surgery.
Results
Malignant tumors were significantly larger than benign tumors (11.1±4.0 cm vs. 6.2±3.4 cm, p<0.001), and postoperative persistence of arterial hypertension was more frequent after removal of malignant than benign tumors (p=0.001). Among the 147 patients without metastatic disease at diagnosis, those who developed metastasis had significantly lower concentrations of urinary catecholamine metabolites per unit of tumor, including vanillylmandelic acid (1.2 vs. 3.7 mg/day/cm, p=0.049), epinephrine (4.5 vs. 168.9 µg/day/cm, p=0.008), and norepinephrine (13.1 vs. 121.8 mg/day/cm, p<0.001). The overall 5-year metastasis-free survival rate was 84.4% and was significantly higher in patients with smaller tumors (≤5.5 vs. >5.5 cm; 90.6% vs. 81.2%, p=0.025) and higher 24-hour secretion of vanillylmandelic acid (>2.1 vs. ≤2.1 mg/day/cm; 94.9% vs. 70.9%, p=0.019).
Conclusions
Large tumor size (>5.5 cm) and minimally elevated 24-hour urinary vanillylmandelic acid (≤2.1 mg/day/cm) were significantly associated with a higher probability of a malignant pheochromocytoma portending a lower metastasis-free survival and mandating more rigorous follow-up after surgery.
doi:10.4111/kju.2011.52.4.241
PMCID: PMC3085615  PMID: 21556209
Adrenal gland neoplasms; Catecholamines; Pheochromocytoma; Tumor burden
6.  AGR2, a mucinous ovarian cancer marker, promotes cell proliferation and migration 
Ovarian cancer is a leading cause of death in women. Early detection of ovarian cancer is essential to decrease mortality. However, the early diagnosis of ovarian cancer is difficult due to a lack of clinical symptoms and suitable molecular diagnostic markers. Thus, identification of meaningful tumor biomarkers with potential clinical application is clearly needed. To search for a biomarker for the early detection of ovarian cancer, we identified human anterior gradient 2 (AGR2) from our systematic analysis of paired normal and ovarian tumor tissue cDNA microarray. We noted a marked overexpression of AGR2 mRNA and protein in early stage mucinous ovarian tumors compared to normal ovarian tissues and serous type ovarian tumors by Western blot analysis and immunohistochemistry. To further elucidate the role of AGR2 in ovarian tumorigenesis, stable 2774 human ovarian cancer cell lines overexpressing AGR2 were established. Forced expression of AGR2 in 2774 cells enhanced the growth and migration of ovarian cancer cells. AGR2 protein was detected in the serum of mucinous ovarian cancer patients by Western blot and ELISA analysis. Thus, AGR2 is a potential biomarker for the diagnosis of mucinous ovarian cancer and an ELISA assay may facilitate the early detection of mucinous ovarian cancer using patient serum.
doi:10.3858/emm.2011.43.2.011
PMCID: PMC3047197  PMID: 21200134
AGR2 protein, human; biological markers; ovarian neoplasms
7.  Preoperative Clinical and Pathological Characteristics of pT0 Prostate Cancer in Radical Prostatectomy 
Korean Journal of Urology  2010;51(6):386-390.
Purpose
To analyze the preoperative clinical and pathological characteristics of patients with pT0 prostate cancer.
Materials and Methods
We retrospectively reviewed the records of 702 patients who underwent radical prostatectomy (RP) at our institution between January 2004 and July 2008 for clinically localized prostate cancer. If there was no evidence of residual tumor in the pathological specimen of the prostate, a patient was staged as pT0. Patients with pT0 disease were compared with a control group of patients who were operated on during the same period.
Results
Overall, 9 (1.3%) patients were staged as pT0 on the pathologic examination. Significant differences were observed between the pT0 group and the control patients in the biopsy Gleason score (p=0.004), the number of positive cores on biopsy (p=0.018), the tumor length of positive cores (p<0.001), and prostate volume (p=0.015). Cutoff values predictive of pT0 tumor status were defined as a biopsy Gleason score sum ≤6, 2 or fewer positive biopsy cores, tumor length on biopsy ≤2 mm, and prostate volume >30 cm3. Whereas 8 of the 9 (88.9%) pT0 patients showed all of these characteristics, only 55 of the 693 (7.9%) control patients fulfilled the criteria. The combination suggested above afforded a sensitivity of 88.8% and a specificity of 92.1% for the prediction of pT0 status.
Conclusions
The frequency of pT0 prostate cancer seen on RP was 1.3%. A combination of clinicopathological features, incorporating a biopsy Gleason score, the number of positive biopsy cores, tumor length on biopsy, and prostate volume, was useful to predict pT0 stage on RP.
doi:10.4111/kju.2010.51.6.386
PMCID: PMC2890054  PMID: 20577604
Biopsy; Neoplasm staging; Prostatectomy; Prostatic neoplasms
8.  A Long-Term Study of the Effects of the Tension-Free Vaginal Tape Procedure for Female Stress Urinary Incontinence on Voiding, Storage, and Patient Satisfaction: A Post-Hoc Analysis 
Korean Journal of Urology  2010;51(1):40-44.
Purpose
We assessed the long-term effects of the tension-free vaginal tape (TVT) procedure for stress urinary incontinence (SUI) on voiding, storage, and patient satisfaction.
Materials and Methods
This retrospective study examined the records of 134 patients who had undergone the TVT procedure for SUI and were followed up for more than 5 years. Voiding function was evaluated by measuring maximum urinary flow rate (MFR), post-void residual urine volume (PVR), and storage function by using a voiding diary. Patients were asked to describe their satisfaction with the operation.
Results
MFR was lower at 1 month compared with the preoperative level, but had recovered to preoperative levels by 5 years postoperatively. However, some patients with >50%, 25-50%, and <25% decreases in the MFR at 1 month postoperatively showed a decrease in the MFR of >50% at 5 years. PVR increased over the 5 postoperative years. Of the patients with urgency and urgency incontinence, 43.8% and 48.1% showed improvement, respectively, whereas new patients developed postoperatively. Thus, the total number of patients with urgency or urgency incontinence remained similar over the 5 years. In those with a changed voiding pattern, patient satisfaction was negatively affected by de novo urgency and urgency incontinence and decreased MFR.
Conclusions
Any obstructive effect of the TVT procedure diminished over time in most patients, although a decrease in the MFR was sustained in some patients. With regard to overactive bladder symptoms, some patients were cured and some patients complained of de novo symptoms. The most major factor affecting patient satisfaction was de novo urgency.
doi:10.4111/kju.2010.51.1.40
PMCID: PMC2855463  PMID: 20414409
Patient satisfaction; Suburethral slings; Stress urinary incontinence
9.  Identification of the DNA Sequence Interacting with Kaposi's Sarcoma-Associated Herpesvirus Viral Interferon Regulatory Factor 1▿  
Journal of Virology  2007;81(22):12680-12684.
Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiological agent of Kaposi's sarcoma. The open reading frame (K9) of KSHV encodes viral interferon regulatory factor 1 (vIRF1), which functions as a repressor of interferon-mediated signal transduction. The amino-terminal region of vIRF1 displays significant homology to the DNA-binding domain of cellular interferon regulatory factors, supporting the theory that the protein interacts with specific DNA sequences. Here, we identify the consensus sequence of vIRF1-binding sites from a pool of random oligonucleotides. Moreover, our data show that vIRF1 interacts with the K3:viral dihydrofolate reductase:viral interleukin 6 promoter region in the KSHV genome.
doi:10.1128/JVI.00556-07
PMCID: PMC2169006  PMID: 17855527
10.  Sumoylation of the Novel Protein hRIPβ Is Involved in Replication Protein A Deposition in PML Nuclear Bodies 
Molecular and Cellular Biology  2005;25(18):8202-8214.
Replication protein A (RPA) is a single-stranded-DNA-binding protein composed of three subunits with molecular masses of 70, 32, and 14 kDa. The protein is involved in multiple processes of eukaryotic DNA metabolism, including DNA replication, repair, and recombination. In Xenopus, Xenopus RPA-interacting protein α has been identified as a carrier molecule of RPA into the nucleus. In this study, human RPA-interacting protein α (hRIPα) and five novel splice isoforms (named hRIPα, hRIPβ, hRIPγ, hRIPδ1, hRIPδ2, and hRIPδ3 according to the lengths of their encoding peptides) were cloned. Among hRIP isoforms, hRIPα and hRIPβ were found to be the major splice isoforms and to show different subcellular localizations. While hRIPα localized to the cytoplasm, hRIPβ was found in the PML nuclear body. Modification of hRIPβ by sumoylation was found to be required for localization to the PML nuclear body. The results of the present work demonstrate that hRIPβ transports RPA into the PML nuclear body and releases RPA upon UV irradiation. hRIPβ thus plays an important role in RPA deposition in PML nuclear bodies and thereby supplements RPA for DNA metabolism.
doi:10.1128/MCB.25.18.8202-8214.2005
PMCID: PMC1234305  PMID: 16135809
11.  Distinct Roles of Cellular Lck and p80 Proteins in Herpesvirus Saimiri Tip Function on Lipid Rafts 
Journal of Virology  2003;77(16):9041-9051.
Lipid rafts are proposed to function as platforms for both receptor signaling and trafficking. Following interaction with antigenic peptides, the T-cell receptor (TCR) rapidly translocates to lipid rafts, where it transmits signals and subsequently undergoes endocytosis. The Tip protein of herpesvirus saimiri (HVS), which is a T-lymphotropic tumor virus, interacts with cellular Lck tyrosine kinase and p80, a WD domain-containing endosomal protein. Interaction of Tip with p80 induces enlarged vesicles and recruits Lck and TCR complex into these vesicles for trafficking. We report here that Tip is constitutively present in lipid rafts and that Tip interaction with p80 but not with Lck is necessary for its efficient localization in lipid rafts. The Tip-Lck interaction was required for recruitment of the TCR complex to lipid rafts, and the Tip-p80 interaction was critical for the aggregation and internalization of lipid rafts. These results suggest the potential mechanism for Tip-mediated TCR downregulation: Tip interacts with Lck to recruit TCR complex to lipid rafts, and it subsequently interacts with p80 to initiate the aggregation and internalization of the lipid raft domain and thereby downregulate the TCR complex. Thus, the signaling and targeting functions of HVS Tip rely on two functionally and genetically separable mechanisms that independently target cellular Lck tyrosine kinase and p80 endosomal protein.
doi:10.1128/JVI.77.16.9041-9051.2003
PMCID: PMC167239  PMID: 12885920
12.  Kaposi's Sarcoma-Associated Herpesvirus Mitochondrial K7 Protein Targets a Cellular Calcium-Modulating Cyclophilin Ligand To Modulate Intracellular Calcium Concentration and Inhibit Apoptosis 
Journal of Virology  2002;76(22):11491-11504.
On viral infection, infected cells can become the target of host immune responses or can go through a programmed cell death process, called apoptosis, as a defense mechanism to limit the ability of the virus to replicate. To prevent this, viruses have evolved elaborate mechanisms to subvert the apoptotic process. Here, we report the identification of a novel antiapoptotic K7 protein of Kaposi's sarcoma-associated herpesvirus (KSHV) which expresses during lytic replication. The KSHV K7 gene encodes a small mitochondrial membrane protein, and its expression efficiently inhibits apoptosis induced by a variety of apoptogenic agents. The yeast two-hybrid screen has demonstrated that K7 targets cellular calcium-modulating cyclophilin ligand (CAML), a protein that regulates the intracellular Ca2+ concentration. Similar to CAML, K7 expression significantly enhances the kinetics and amplitudes of the increase in intracellular Ca2+ concentration on apoptotic stimulus. Mutational analysis showed that K7 interaction with CAML is required for its function in the inhibition of apoptosis. This indicates that K7 targets cellular CAML to increase the cytosolic Ca2+ response, which consequently protects cells from mitochondrial damage and apoptosis. This is a novel viral antiapoptosis strategy where the KSHV mitochondrial K7 protein targets a cellular Ca2+-modulating protein to confer resistance to apoptosis, which allows completion of the viral lytic replication and, eventually, maintenance of persistent infection in infected host.
doi:10.1128/JVI.76.22.11491-11504.2002
PMCID: PMC136794  PMID: 12388711
13.  Viral Interferon Regulatory Factor 1 of Kaposi's Sarcoma-Associated Herpesvirus Binds to p53 and Represses p53-Dependent Transcription and Apoptosis 
Journal of Virology  2001;75(13):6193-6198.
Kaposi's sarcoma-associated herpesvirus (KSHV) is related to the development of Kaposi's sarcoma. Open reading frame K9 of KSHV encodes viral interferon regulatory factor 1 (vIRF1), which functions as a repressor of interferon- and IRF1-mediated signal transduction. In addition, vIRF1 acts as an oncogene to induce cellular transformation. Here we show that vIRF1 directly associates with the tumor suppressor p53 and represses its functions. The vIRF1 interaction domains of p53 are the DNA binding domain (amino acids [aa] 100 to 300) and the tetramerization domain (aa 300 to 393). p53 interacts with the central region (aa 152 to 360) of vIRF1. vIRF1 suppresses p53-dependent transcription and deregulates its apoptotic activity. These results suggest that vIRF1 may regulate cellular function by inhibiting p53.
doi:10.1128/JVI.75.13.6193-6198.2001
PMCID: PMC114335  PMID: 11390621
14.  The K-bZIP Protein from Kaposi's Sarcoma-Associated Herpesvirus Interacts with p53 and Represses Its Transcriptional Activity 
Journal of Virology  2000;74(24):11977-11982.
Kaposi's sarcoma-associated herpesvirus (KSHV) is a gammaherpesvirus that has been implicated in the pathogenesis of Kaposi's sarcoma. KSHV encodes K-bZIP (open reading frame K8), a protein that belongs to the basic region-leucine zipper (bZIP) family of transcription factors. Here we show that K-bZIP associates with the cellular transcription factor p53 directly in vitro and in vivo. This interaction requires the bZIP domain of K-bZIP and the carboxy-terminal region (amino acids 300 to 393) of p53. We also show that K-bZIP represses the transcriptional activity of p53 which is required for apoptosis of the host cell. These results imply that K-bZIP blocks p53-mediated host cell death through its interaction with p53.
PMCID: PMC112483  PMID: 11090200

Results 1-14 (14)