• OCIAD1
• organelle interaction
• organelle proteomics
• peroxisomes

• Animals
• Mice
• Proteome
• Peroxisomes
• Research Design
• Mitochondria
• Mass Spectrometry

• 397476530, 449879597 Deutsche Forschungsgemeinschaft

• HTATIP2/TIP30
• RNA-seq
• T cells
• gene expression
• genome-wide association study (GWAS)
• pediatrics
• type 1 diabetes

• CC3/TIP30
• HTATIP2/TIP30
• Contact dermatitis

• Acetyltransferases/blood
• Adult
• Aged
• Aged, 80 and over
• Biomarkers, Tumor/blood
• Case-Control Studies
• Cross-Sectional Studies
• Dermatitis, Contact/blood
• Dermatitis, Contact/pathology
• Enzyme-Linked Immunosorbent Assay
• Female
• HIV-1/metabolism
• HIV-1/pathogenicity
• Humans
• Male
• Middle Aged
• Suppressor of Cytokine Signaling 1 Protein
• Transcription Factors/blood

• Expression pattern
• Fish
• Function
• Gonadal development

• Animals
• Apoptosis
• Disorders of Sex Development
• Eels/genetics
• Female
• Fish Proteins/genetics
• Fishes
• Hydrogen Peroxide
• Phylogeny
• RNA, Messenger/genetics
• Smegmamorpha/physiology

• Anti-metastasis
• Multiple regulation
• NM23-H1
• Therapeutic intervention

• DDP resistance
• SIVA-1
• gastric cancer

• Apoptosis/drug effects
• Apoptosis/genetics
• Apoptosis Regulatory Proteins/genetics
• Cell Line, Tumor
• Cell Proliferation/drug effects
• Cell Proliferation/genetics
• Cisplatin/pharmacology
• Drug Resistance, Neoplasm/genetics
• Gene Expression
• Genetic Vectors/genetics
• Humans
• Lentivirus/genetics
• Proto-Oncogene Proteins c-bcl-2/metabolism
• Proto-Oncogene Proteins c-mdm2/metabolism
• Stomach Neoplasms/pathology
• Tumor Protein p73/metabolism
• Tumor Suppressor Protein p14ARF/metabolism
• Tumor Suppressor Protein p53/metabolism
• bcl-X Protein/metabolism

• 81660416 Natural Science Foundation of China

• HTATIP2
• epithelial-mesenchymal transition
• hypoxia inducible factors
• tumor hypoxia
• tumor metabolic plasticity

Pathological cardiac overload induces myocardial protein synthesis and hypertrophy, which predisposes to heart failure. To inhibit hypertrophy therapeutically, the identification of negative regulators of cardiomyocyte protein synthesis is needed. Here, we identified the tumor suppressor protein TIP30 as novel inhibitor of cardiac hypertrophy and dysfunction. Reduced TIP30 levels in mice entailed exaggerated cardiac growth during experimental pressure overload, which was associated with cardiomyocyte cellular hypertrophy, increased myocardial protein synthesis, reduced capillary density, and left ventricular dysfunction. Pharmacological inhibition of protein synthesis improved these defects. Our results are relevant for human disease, since we found diminished cardiac TIP30 levels in samples from patients suffering from end‐stage heart failure or hypertrophic cardiomyopathy. Importantly, therapeutic overexpression of TIP30 in mouse hearts inhibited cardiac hypertrophy and improved left ventricular function during pressure overload and in cardiomyopathic mdx mice. Mechanistically, we identified a previously unknown anti‐hypertrophic mechanism, whereby TIP30 binds the eukaryotic elongation factor 1A (eEF1A) to prevent the interaction with its essential co‐factor eEF1B2 and translational elongation. Therefore, TIP30 could be a therapeutic target to counteract cardiac hypertrophy.

• cardiac hypertrophy
• cardiomyopathy
• heart failure
• protein synthesis
• translational elongation

• NONHSAT076754
• invasion
• long non-coding RNA
• metastasis
• ovarian cancer

Non-small-cell lung cancer (NSCLC) is a deadly malignancy with a high prevalence worldwide. A reliable biomarker that can predict the prognosis is required to determine the therapeutic strategy. TIP30 was first identified as a tumor suppressor. A number of mechanistic studies indicated that the downregulation of TIP30 enhances the stemness, migration and survival of NSCLC cells. However, the clinical relevance of TIP30 for the prognosis of NSCLC is unknown. From a meta-analysis of public microarray datasets, we showed the upregulation of TIP30 mRNA expression was associated with worse overall survival of NSCLC patients, which contradicted the tumor suppressive role of TIP30. It is worth noting that the TIP30 mRNA expression was not correlated with its protein expression in 15 NSCLC cell lines. The results from the immunohistochemistry of a tissue microarray showed the downregulation of the TIP30 protein expression was associated with a higher risk of metastasis. In addition, the decrease in TIP30 protein was correlated with worse overall and progression-free survival of the NSCLC patients. Multivariate analysis suggested the loss of TIP30 protein was an independent factor to predict the poor prognosis of NSCLC. Our data indicated that TIP30 protein, not mRNA, would be a potential prognostic biomarker of NSCLC.

• Tat-interacting protein 30 (TIP30)
• biomarker
• non-small-cell lung cancer (NSCLC)
• precision medicine

Siva-1 is a typical apoptotic protein commonly activated by the p53 tumor suppressor protein and should therefore participate in a barrier against the development of cancer. It has proapoptotic activities in various cell systems. Recent findings suggest that Siva-1 possesses several other apoptosis-independent functions and interacts with many other proteins not directly involved in apoptosis. It harbors the ARF E3 ubiquitin protein ligase activity, a property that is clearly prooncogenic and leads to p53 degradation through the upregulation of the Hdm2 protein level. Surprisingly, recent evidence shows that Siva-1 absence prevents the development of non-small cell lung carcinomas in a mouse model and reveals the oncogenic roles in the same types of human cells, indicating its unique function as an oncogene in the cell context-dependent manner. Herein, we review reported activities of Siva-1 in various experimental settings and comment on its ambiguous function in tumor biology.

• CD27
• NSCLC
• Siva-1
• apoptosis
• p53

Lung cancer patients with human immunodeficiency virus (HIV) have a poorer prognosis than do patients without HIV infection. HIV1 Tat is a secreted viral protein that penetrates the plasma membrane and interacts with a number of proteins in non‐HIV‐infected cells. The loss of function of Tat‐interacting protein 30 (TIP30) has been linked to metastasis in non‐small cell lung cancer (NSCLC). However, it is unknown how the interaction of HIV1 Tat with TIP30 regulates the metastasis of NSCLC cells. In this study, the overexpression of TIP30 decreased tumor growth factor‐β‐induced epithelial‐to‐mesenchymal transition (EMT) and invasion of NSCLC cells, whereas the knockdown of TIP30 promoted EMT, invasion and stemness. Exposure to recombinant HIV1 Tat proteins promoted EMT and invasion. A mechanistic study showed that the interaction of HIV1 Tat with TIP30 blocked the binding of TIP30 to importin‐β, which is required for the nuclear translocation of Snail. Indeed, the loss of TIP30 promoted the nuclear translocation of Snail. In vivo studies demonstrated that the overexpression of TIP30 inhibited the metastasis of NSCLC cells. In contrast, the coexpression of HIV1 Tat and TIP30 diminished the inhibitory effect of TIP30 on metastasis. Immunohistochemistry confirmed that TIP30 overexpression reduced the nuclear localization of Snail, whereas the coexpression of HIV1 Tat and TIP30 increased nuclear Snail in metastatic tumors. In conclusion, the binding of HIV1 Tat to TIP30 enhanced EMT and metastasis by regulating the nuclear translocation of Snail. Targeting Tat‐interacting proteins may be a potential therapeutic strategy to prevent metastasis in NSCLC patients with HIV infection.

• Snail
• Tat-interacting protein
• epithelial-to-mesenchymal transition
• non-small cell lung cancer
• nuclear translocation

Tat-interacting protein 30 (TIP30) has been reported to be a tumor suppressor, with reduced or absent expression in various tumors. However, its role in bladder urothelial cancer (BUC) has not been investigated. Therefore, herein, we investigated the expression of TIP30 protein in BUC and normal bladder mucosa and the clinical significance of TIP30 expression in the prognosis of BUC.

We reviewed data from 79 cases of BUC and 15 adjacent tissue samples from 79 patients treated at our institution between 2004 and 2007. TIP30 expression was examined by immunohistochemistry. The relationship between TIP30 expression and tumor stage, histological grade, and survival was analyzed. Differences between groups were evaluated using the t-test or matched-pairs test, and differences in the survival rates were analyzed with the log-rank test.

TIP30 protein expression was significantly reduced in BUC tissue (t = −6.91, P < 0.05) compared with normal tissue samples, and in invasive bladder cancer (t = 10.89, P < 0.05) compared with superficial bladder cancer. TIP30 protein expression differed significantly among different differentiated groups classified either according to the World Health Organization (2004, F = 17.48, P < 0.01) or World Health Organization (1973, F = 10.68, P < 0.01). TIP30 protein expression was significantly reduced in high-grade papillary urothelial carcinoma compared with papillary urothelial neoplasm of low malignant potential (P < 0.05) and low-grade papillary urothelial carcinoma (P < 0.05). Meanwhile, TIP30 protein expression was significantly reduced in Grade III BUC, compared with Grade I (P < 0.05) and Grade II (P < 0.05). Patients with low TIP30 expression showed a higher incidence of disease progression than those with high TIP30 expression (t = 2.63, P < 0.05). Kaplan-Meier survival analysis showed a strong positive relationship between TIP30 expression and overall survival (OS) (χ² = 17.29, P < 0.05).

TIP30 expression was associated with clinical tumor stage in BUC, suggesting that it might play an important role in disease progression. Furthermore, TIP30 might predict postoperative OS. Thus, its evaluation might be useful for predicting prognosis.

The present study aimed to evaluate the diagnostic and prognostic value of Tat-interacting protein 30 (HTATIP2/TIP30) levels alone and in combination with α-fetoprotein (AFP) for the evaluation of hepatocellular carcinoma (HCC) patients. ELISA and immunohistochemical measurements on the serum and tissue of HTATIP2/TIP30 protein from HCC patients and normal controls were made. Receiver operating characteristic (ROC) curve analyses of AFP and HTATIP2/TIP30 were performed, as well as logistic regression analysis of APF combined with HTATIP2/TIP30. Log-rank analysis was used to correlate the prognosis with various levels of HTATIP2/TIP30. HTATIP2/TIP30 levels were significantly lower in the HCC group compared with the control group (4.50±2.63 vs. 9.50±2.04 ng/ml, P<0.001). ROC analysis revealed an optimal cut-off point at 7.27 ng/ml HTATIP2/TIP30 for separating the HCC from the control groups. The sensitivity and specificity were 84.6 and 93.7% (P<0.001), respectively. ROC areas of HTATIP2/TIP30 (0.928, P<0.001) were significantly higher than those for AFP (P<0.001). The area under the curve of the HTATIP2/TIP30 and AFP combination was 0.950 (P<0.001). Log-rank tests revealed that the recurrence-free survival time of the group with HTATIP2/TIP30>5.71 ng/ml was significantly higher than that of the control group (P<0.001). This is the first study to demonstrate that HTATIP2/TIP30 levels in serum may be an effective biomarker for the diagnosis and prognosis of HCC.

• Tat-interacting protein 30 level
• biomarker
• hepatocellular carcinoma
• serum
• α-fetoprotein

Altered expression of TIP30, a tumor suppressor, has been observed in many cancers. In this study, we have evaluated the expression of TIP30 in the tissues of 209 hepatocellular carcinomas (HCC) and their adjacent tissues by using a high‐density tissue microarray, and analyzed its correlation with the clinical pathological parameters of the patients. The results revealed negative or weak expression of TIP30 in 43.5% (91/209) of the HCC tissues, and in only 27% (56/209) of the adjacent tissues. The expression level of TIP30 in HCC was inversely correlated with serum alpha‐fetoprotein (AFP) levels, HBV infection, and tumor differentiation. Multivariate analysis for survival indicated that serum HBV infection was the most significant predictor of poor prognosis in HCC (P = 0.0023), and TIP30 expression and tumor differentiation were also independent indicators in this respect (P = 0.0364 and P = 0.0397, respectively). Patients with medium or high expression levels of TIP30 (TIP30^++/+++) had a better 5‐year overall survival rate than those with low/negative (TIP30^+/−) expression (P < 0.001). TIP30^+/−/HBV⁺ patients had the worst 5‐year overall survival rate, whereas TIP30^++/+++/HBV⁻ patients had the best. To further explore the correlation between TIP30 and HBV infection in HCC, HBV⁺ hepatoblastoma cell‐line HepG2 2.2.15 and HCC cell‐line Hep3B were used. Upon silencing of HBV, we observed an upregulation of TIP30 and decreased cell proliferation. In the in vivo studies, we found that the mice inoculated with HepG2 2.2.15 cells with HBV silencing had a prolonged tumor latency and a longer life span, as compared to the control mice inoculated with untreated control cells. In conclusion, the results suggest that downregulation of TIP30 may result from HBV infection, and subsequently promotes the progression of HCC.

• HBV
• Survival
• TIP30
• hepatocellular carcinomas
• tumor suppressor

• Acetyltransferases/genetics
• Adult
• Aged
• Animals
• Carcinoma, Hepatocellular/diagnosis
• Carcinoma, Hepatocellular/etiology
• Carcinoma, Hepatocellular/mortality
• Cell Line, Tumor
• Disease Models, Animal
• Female
• Gene Expression Regulation, Neoplastic
• Gene Expression Regulation, Viral
• Hepatitis B/complications
• Hepatitis B/diagnosis
• Hepatitis B Surface Antigens/genetics
• Hepatitis B virus/genetics
• Heterografts
• Humans
• Kaplan-Meier Estimate
• Liver Neoplasms/diagnosis
• Liver Neoplasms/etiology
• Liver Neoplasms/mortality
• Male
• Mice
• Middle Aged
• Neoplasm Grading
• Neoplasm Staging
• Prognosis
• RNA Interference
• RNA, Small Interfering/genetics
• Retrospective Studies
• Transcription Factors/genetics

• R21 CA117116 NCI NIH HHS

We previously found that a low dose of sorafenib had a prometastatic effect on hepatocellular carcinoma (HCC), which was caused by downregulation of TIP30 expression. More recently, metformin has been shown to have potential as a preventive and therapeutic agent for different cancers, including HCC. This study evaluated whether the combination of sorafenib and metformin is sufficient to revert the expression of TIP30, thereby simultaneously reducing lung metastasis and improving survival. Our data show that the combination of sorafenib and metformin inhibits proliferation and invasion in vitro, prolongs median survival, and reduces lung metastasis of HCC in vivo. This effect is closely associated with the upregulation of TIP30, partly through activating AMP‐activated protein kinase. Thioredoxin, a prometastasis factor, is negatively regulated by TIP30 and plays an essential role during the process of HCC metastasis. Overall, our results suggest that metformin might be a potent enhancer for the treatment of HCC by using sorafenib.

• Hepatocellular carcinoma
• human TIP30 protein
• metformin
• sorafenib
• thioredoxins

Glioma is an aggressive malignancy with limited effective treatment and poor prognosis. Therefore, the identification of novel prognostic markers and effective therapeutic targets is important for the treatment of human glioma. TIP30 is a tumor suppressor involved in the regulation of numerous cellular processes, including tumor cell growth, metastasis, and angiogenesis in various human cancers. The present study investigated whether Tat-interacting protein (TIP)30 was able to regulate tumorigenesis and predict the clinical outcome of patients with glioma. A total of 92 human glioma tissue samples and 10 normal brain tissue samples were examined by immunostaining. The results indicated that the expression levels of TIP30 significantly decreased in glioma tissue samples. as compared with normal brain tissue samples. Furthermore, TIP30 expression was inversely correlated with tumor histological classification, pathological grade, tumor size, and epidermal growth factor receptor (EGFR) expression; however, no association was detected between TIP30 expression and patient age and gender. In addition, patients with positive TIP30 expression exhibited significantly longer median overall survival rates, as compared with those with negative TIP30 expression. In vitro experiments revealed that upregulation of TIP30 expression by lentiviral vector transfection inhibited cell growth and induced cell apoptosis, as determined by MTT assay and Annexin V-fluorescein isothiocyanate staining, respectively. In addition, TIP30 expression markedly attenuated cell migration and invasion, as determined by wound healing and transwell assays. Upregulation of TIP30 expression in glioma cells decreased the expression levels of EGFR and its associated downstream molecules phosphorylated extracellular signal-regulated kinases (ERK) and phosphorylated AKT, as determined by western blot analysis. The results of the present study indicated that TIP30 may suppress oncogenesis and glioma progression, thereby improving the prognosis of patients with glioma. Therefore, TIP30 may prove useful as a prognostic biomarker, and as a potential target for glioma therapy.

• Laryngeal squamous carcinoma
• TIP30
• p53
• survival

• ESCC
• Hypermethylation
• TIP30
• miR-10b

The early growth response transcription factor Egr-1 controls cell specific responses to proliferation, differentiation and apoptosis. Expression of Egr-1 and downstream transcription is closely controlled and cell specific upregulation induced by processes such as hypoxia and ischemia has been previously linked to multiple aspects of cardiovascular injury. In this study, we showed constitutive expression of Egr-1 in cultured human ventricular cardiac fibroblasts, used adenoviral mediated gene transfer to study the effects of continuous Egr-1 overexpression and studied downstream transcription by Western blotting, immunohistochemistry and siRNA transfection. Apoptosis was assessed by fluorescence microscopy and flow cytometry in the presence of caspase inhibitors. Overexpression of Egr-1 directly induced apoptosis associated with caspase activation in human cardiac fibroblast cultures in vitro assessed by fluorescence microscopy and flow cytometry. Apoptotic induction was associated with a caspase activation associated loss of mitochondrial membrane potential and transient downstream transcriptional up-regulation of the pro-apoptotic gene product Siva-1. Suppression of Siva-1 induction by siRNA partially reversed Egr-1 mediated loss of cell viability. These findings suggest a previously unknown role for Egr-1 and transcriptional regulation of Siva-1 in the control of cardiac accessory cell death.

• Apoptosis
• Apoptosis Regulatory Proteins/genetics
• Apoptosis Regulatory Proteins/metabolism
• Cell Line
• Early Growth Response Protein 1/genetics
• Early Growth Response Protein 1/metabolism
• Fibroblasts/metabolism
• Heart Ventricles/cytology
• Humans
• RNA, Messenger/genetics
• RNA, Messenger/metabolism
• Up-Regulation

• gst pull-down assay
• p53
• protein-protein interaction
• surface plasmon resonance
• tip30

• Acetyltransferases/genetics
• Acetyltransferases/metabolism
• Binding Sites
• Cytoplasm/metabolism
• ELAV Proteins/genetics
• ELAV Proteins/metabolism
• Humans
• Surface Plasmon Resonance
• Transcription Factors/genetics
• Transcription Factors/metabolism
• Tumor Suppressor Protein p53/genetics
• Tumor Suppressor Protein p53/metabolism

Homeobox genes encode transcription factors impacting key developmental processes including embryogenesis, organogenesis, and cell differentiation. Reflecting their tight transcriptional control, homeobox genes are often embedded in large non-coding, cis-regulatory regions, containing tissue specific elements. In T-cell acute lymphoblastic leukemia (T-ALL) homeobox genes are frequently deregulated by chromosomal aberrations, notably translocations adding T-cell specific activatory elements. NKX3-1 is a prostate specific homeobox gene activated in T-ALL patients expressing oncogenic TAL1 or displaying immature T-cell characteristics. After investigating regulation of NKX3-1 in primary cells and cell lines, we report its ectopic expression in T-ALL cells independent of chromosomal rearrangements. Using siRNAs and expression profiling, we exploited NKX3-1 positive T-ALL cell lines as tools to investigate aberrant activatory mechanisms. Our data confirmed NKX3-1 activation by TAL1/GATA3/LMO and identified LYL1 as an alternative activator in immature T-ALL cells devoid of GATA3. Moreover, we showed that NKX3-1 is directly activated by early T-cell homeodomain factor MSX2. These activators were regulated by MLL and/or by IL7-, BMP4- and IGF2-signalling. Finally, we demonstrated homeobox gene SIX6 as a direct leukemic target of NKX3-1 in T-ALL. In conclusion, we identified three major mechanisms of NKX3-1 regulation in T-ALL cell lines which are represented by activators TAL1, LYL1 and MSX2, corresponding to particular T-ALL subtypes described in patients. These results may contribute to the understanding of leukemic transcriptional networks underlying disturbed T-cell differentiation in T-ALL.

Lung adenocarcinoma, the most common type of human non-small cell lung cancer (NSCLC), frequently overexpresses EGFR. However, the mechanisms underlying EGFR overexpression are not completely understood. Recent studies have identified that decreased expression of TIP30 is associated with the metastasis of human NSCLCs, but a causative relationship between TIP30 deficiency and NSCLC development remains unclear. We show here that Tip30 deletion leads to spontaneous development of lung adenomas and adenocarcinomas in mice. Lung tumor development was preceded by aberrant expansion of bronchioalveolar stem/progenitor and alveolar type II cells, as well as increased expression of EGFR and its downstream signaling factors in the lung of Tip30^−/− mice. Moreover, TIP30 knockdown in human lung adenocarcinoma cells resulted in prolonged EGFR activity in early endosomes, delayed EGFR degradation, increased EGFR nuclear localization, leading to up-regulated pAKT and pERK1/2 expression. Importantly, in human lung adenocarcinomas, low TIP30 expression correlates with prolonged patient overall and post-progression survival times. Together, these results suggest that TIP30 functions as a tumor suppressor to inhibit EGFR cytoplasmic and nuclear signaling and suppress adenocarcinogenesis in the lung and highlight the potential of therapeutic strategies aiming at inhibiting EGFR signaling for patients with low TIP30 expression lung adenocarcinoma.

Efficient membrane fusion has been successfully mimicked in vitro using artificial membranes and a number of cellular proteins that are currently known to participate in membrane fusion. However, these proteins are not sufficient to promote efficient fusion between biological membranes, indicating that critical fusogenic factors remain unidentified. We have recently identified a TIP30 protein complex containing TIP30, acyl-CoA synthetase long-chain family member 4 (ACSL4) and Endophilin B1 (Endo B1) that promotes the fusion of endocytic vesicles with Rab5a vesicles, which transport endosomal acidification enzymes vacuolar (H⁺)-ATPases (V-ATPases) to the early endosomes in vivo. Here, we demonstrate that the TIP30 protein complex facilitates the fusion of endocytic vesicles with Rab5a vesicles in vitro. Fusion of the two vesicles also depends on arachidonic acid, coenzyme A and the synthesis of arachidonyl-CoA by ACSL4. Moreover, the TIP30 complex is able to transfer arachidonyl groups onto phosphatidic acid (PA), producing a new lipid species that is capable of inducing close contact between membranes. Together, our data suggest that the TIP30 complex facilitates biological membrane fusion through modification of PA on membranes.

• Acetyltransferases/metabolism
• Acylation
• Acyltransferases/metabolism
• Arachidonic Acid/metabolism
• Coenzyme A/metabolism
• Coenzyme A Ligases/metabolism
• Hep G2 Cells
• Humans
• Membrane Fusion
• Phosphatidic Acids/metabolism
• Protein Binding
• Recombinant Proteins/metabolism
• Transcription Factors/metabolism
• Transport Vesicles/metabolism
• Transport Vesicles/ultrastructure
• rab5 GTP-Binding Proteins/metabolism

• R01 DK066110 NIDDK NIH HHS
• R01 DK066110-01 NIDDK NIH HHS

• endocytosis
• hepatocyte
• signal transduction
• trafficking
• tumor suppressor
• vesicles
• egfr
• endophilin b1
• rab5a
• tip30

• Acetyltransferases/genetics
• Acetyltransferases/metabolism
• Acyltransferases/genetics
• Acyltransferases/metabolism
• Animals
• Coenzyme A Ligases/genetics
• Coenzyme A Ligases/metabolism
• Endocytosis/physiology
• Endosomes/genetics
• Endosomes/metabolism
• ErbB Receptors/genetics
• ErbB Receptors/metabolism
• Golgi Apparatus/genetics
• Golgi Apparatus/metabolism
• Hep G2 Cells
• Hepatocytes/metabolism
• Humans
• Mice
• Mice, Knockout
• Multienzyme Complexes/genetics
• Multienzyme Complexes/metabolism
• Protein Transport/physiology
• Repressor Proteins/genetics
• Repressor Proteins/metabolism
• Signal Transduction/physiology
• Transcription Factors/genetics
• Transcription Factors/metabolism
• Tumor Suppressor Proteins/genetics
• Tumor Suppressor Proteins/metabolism
• rab5 GTP-Binding Proteins/genetics
• rab5 GTP-Binding Proteins/metabolism

• R01 DK066110 NIDDK NIH HHS
• R01 DK066110-01 NIDDK NIH HHS

• Acetyltransferases/genetics
• Acetyltransferases/metabolism
• Aged
• Aged, 80 and over
• Cell Movement
• Colorectal Neoplasms/metabolism
• Down-Regulation
• Female
• Gene Expression Regulation, Neoplastic/physiology
• Humans
• Male
• Middle Aged
• Mutation
• Neoplasm Invasiveness
• Promoter Regions, Genetic
• Transcription Factors/genetics
• Transcription Factors/metabolism

The pro-apoptotic protein CC3/TIP30 has an unusual cellular function as an inhibitor of nucleocytoplasmic transport. This function is likely to be activated under conditions of stress. A number of studies support the notion that CC3 acts as a tumor and metastasis suppressor in various types of cancer. The yeast homolog of CC3 is likely to be involved in responses to DNA damage. Here we examined the potential role of CC3 in regulation of cellular responses to genotoxic stress.

We found that forced expression of CC3 in CC3-negative cells strongly delays the repair of UV-induced DNA damage. Exogenously introduced CC3 negatively affects expression levels of DDB2/XPE and p21CIP1, and inhibits induction of c-FOS after UV exposure. In addition, exogenous CC3 prevents the nuclear accumulation of P21CIP in response to UV. These changes in the levels/localization of relevant proteins resulting from the enforced expression of CC3 are likely to contribute to the observed delay in DNA damage repair. Silencing of CC3 in CC3-positive cells has a modest delaying effect on repair of the UV induced damage, but has a much more significant negative affect on the translesion DNA synthesis after UV exposure. This could be related to the higher expression levels and increased nuclear localization of p21CIP1 in cells where expression of CC3 is silenced. Expression of CC3 also inhibits repair of oxidative DNA damage and leads to a decrease in levels of nucleoredoxin, that could contribute to the reduced viability of CC3 expressing cells after oxidative insult.

Manipulation of the cellular levels of CC3 alters expression levels and/or subcellular localization of proteins that exhibit nucleocytoplasmic shuttling. This results in altered responses to genotoxic stress and adversely affects DNA damage repair by affecting the recruitment of adequate amounts of required proteins to proper cellular compartments. Excess of cellular CC3 has a significant negative effect on DNA repair after UV and oxidant exposure, while silencing of endogenous CC3 slightly delays repair of UV-induced damage.

Biomarkers of breast cancer are necessary for prognosis and prediction to chemotherapy. Prognostic biomarkers provide information regarding outcome irrespective of therapy, while predictive biomarkers provide information regarding response to therapy. Candidate prognostic biomarkers for breast cancers are growth factor receptors, steroid receptors, Ki-67, cyclins, urokinase plasminogen activator, p53, p21, pro- and anti-apoptotic factors, BRCA1 and BRCA2. But currently, the predictive markers are Estrogen and Progesterone receptors responding to endocrine therapy, and HER-2 responding to herceptin. But there are numerous breast cancer cases, where tamoxifen is ineffective even after estrogen receptor positivity. This lead to search of new prognostic and predictive markers and the number of potential markers is constantly increasing due to proteomics and genomics studies. However, most biomarkers individually have poor sensitivity or specificity, or other clinical value. It can be resolved by studying various biomarkers simultaneously, which will help in better prognosis and increasing sensitivity for chemotherapeutic agents. This review is focusing on growth factor receptors, apoptosis markers, signaling cascades, and their correlation with other associated biomarkers in breast cancers. As our knowledge regarding molecular biomarkers for breast cancer increases, prognostic indices will be developed that combine the predictive power of individual molecular biomarkers with specific clinical and pathologic factors. Rigorous comparison of these existing as well as emerging markers with current treatment selection is likely to see an escalation in an era of personalized medicines to ensure the breast cancer patients receive optimal treatment. This will also solve the treatment modalities and complications related to chemotherapeutic regimens.

• apoptosis
• chemotherapy
• estrogen
• growth factor receptor
• mitogen-activated protein kinase
• prognostic markers

Short-chain dehydrogenases/reductases (SDRs) constitute a large family of NAD(P)(H)-dependent oxidoreductases, sharing sequence motifs and displaying similar mechanisms. SDR enzymes have critical roles in lipid, amino acid, carbohydrate, cofactor, hormone and xenobiotic metabolism as well as in redox sensor mechanisms. Sequence identities are low, and the most conserved feature is an α/β folding pattern with a central beta sheet flanked by 2–3 α-helices from each side, thus a classical Rossmannfold motif for nucleotide binding. The conservation of this element and an active site, often with an Asn-Ser-Tyr-Lys tetrad, provides a platform for enzymatic activities encompassing several EC classes, including oxidoreductases, epimerases and lyases. The common mechanism is an underlying hydride and proton transfer involving the nicotinamide and typically an active site tyrosine residue, whereas substrate specificity is determined by a variable C-terminal segment. Relationships exist with bacterial haloalcohol dehalogenases, which lack cofactor binding but have the active site architecture, emphasizing the versatility of the basic fold in also generating hydride transfer-independent lyases. The conserved fold and nucleotide binding emphasize the role of SDRs as scaffolds for an NAD(P)(H) redox sensor system, of importance to control metabolic routes, transcription and signalling.

• Adaptor Proteins, Signal Transducing/genetics
• Adaptor Proteins, Signal Transducing/metabolism
• Animals
• Apoptosis/physiology
• Apoptosis Regulatory Proteins
• CD4 Antigens/genetics
• CD4 Antigens/metabolism
• CD4-Positive T-Lymphocytes/cytology
• CD4-Positive T-Lymphocytes/immunology
• CD4-Positive T-Lymphocytes/physiology
• Cell Line
• HIV-1/metabolism
• HIV-1/ultrastructure
• Humans
• Intracellular Signaling Peptides and Proteins/genetics
• Intracellular Signaling Peptides and Proteins/metabolism
• Ligands
• Protein Binding
• Recombinant Fusion Proteins/genetics
• Recombinant Fusion Proteins/metabolism
• Sequestosome-1 Protein
• Signal Transduction/physiology
• Two-Hybrid System Techniques

• Androgens/metabolism
• Apoptosis/genetics
• Cell Line, Tumor
• Cell Transformation, Neoplastic/genetics
• Disease Progression
• Down-Regulation
• Gene Expression Profiling/methods
• Gene Expression Regulation, Neoplastic
• Gene Regulatory Networks
• Humans
• Immunohistochemistry
• Male
• Neoplasms, Hormone-Dependent/genetics
• Neoplasms, Hormone-Dependent/metabolism
• Oligonucleotide Array Sequence Analysis
• Phenotype
• Prostatic Neoplasms/genetics
• Prostatic Neoplasms/metabolism
• Protein Phosphatase 2/genetics
• RNA, Messenger/analysis
• Reproducibility of Results
• Reverse Transcriptase Polymerase Chain Reaction
• Signal Transduction/genetics

• P20 RR016469 NCRR NIH HHS
• R01 CA088184 NCI NIH HHS
• R01 CA088184-09 NCI NIH HHS