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1.
Stem Cells Dev ; 33(3-4): 89-103, 2024 Feb.
Article in English | MEDLINE | ID: mdl-38164089

ABSTRACT

Mesenchymal stem cells (MSCs) directly differentiate into neurons and endothelial cells after transplantation, and their secretome has considerable potential for treating brain injuries. Previous studies have suggested that the effects of MSCs priming with exposure to hypoxia, cytokines, growth factors, or chemical agents could optimize the paracrine potency and therapeutic potential of MSCs. Studies have suggested that thrombin-primed Wharton's Jelly-derived mesenchymal stem cells (Th.WJ-MSCs) significantly enhance the neuroprotective beneficial effects of naive MSCs in brain injury such as hypoxic-ischemic brain injury (HIE) and intraventricular hemorrhage (IVH). This study aimed to characterize WJ-MSCs in terms of stem cell markers, differentiation, cell proliferation, and paracrine factors by comparing naive and Th.WJ-MSCs. We demonstrated that compared with naive MSCs, Th.MSCs significantly enhanced the neuroprotective effects in vitro. Moreover, we identified differentially expressed proteins in the conditioned media of naive and Th.WJ-MSCs by liquid chromatography-tandem mass spectrometry analysis. Secretome analysis of the conditioned medium of WJ-MSCs revealed that such neuroprotective effects were mediated by paracrine effects with secretomes of Th.WJ-MSCs, and hepatocyte growth factor was identified as a key paracrine mediator. These results can be applied further in the preclinical and clinical development of effective and safe cell therapeutics for brain injuries such as HIE and IVH.


Subject(s)
Brain Injuries , Mesenchymal Stem Cells , Neuroprotective Agents , STAT3 Transcription Factor , Wharton Jelly , Humans , Hepatocyte Growth Factor/metabolism , Neuroprotective Agents/pharmacology , Thrombin/pharmacology , Thrombin/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Endothelial Cells/metabolism , Cells, Cultured , Signal Transduction , Cell Differentiation , Immunologic Factors/metabolism , Brain Injuries/metabolism , Cell Proliferation
2.
Aging (Albany NY) ; 14(22): 8944-8969, 2022 11 29.
Article in English | MEDLINE | ID: mdl-36446389

ABSTRACT

Mismatches between pre-clinical and clinical results of stem cell therapeutics for ischemic stroke limit their clinical applicability. To overcome these discrepancies, precise planning of pre-clinical experiments that can be translated to clinical trials and the scientific elucidation of treatment mechanisms is important. In this study, adult human neural stem cells (ahNSCs) derived from temporal lobe surgical samples were used (to avoid ethical and safety issues), and their therapeutic effects on ischemic stroke were examined using middle cerebral artery occlusion animal models. 5 × 105 ahNSCs was directly injected into the lateral ventricle of contralateral brain hemispheres of immune suppressed rat stroke models at the subacute phase of stroke. Compared with the mock-treated group, ahNSCs reduced brain tissue atrophy and neurological sensorimotor and memory functional loss. Tissue analysis demonstrated that the significant therapeutic effects were mediated by the neuroprotective and pro-angiogenic activities of ahNSCs, which preserved neurons in ischemic brain areas and decreased reactive astrogliosis and microglial activation. The neuroprotective and pro-angiogenic effects of ahNSCs were validated in in vitro stroke models and were induced by paracrine factors excreted by ahNSCs. When the JAK2/STAT3 signaling pathway was inhibited by a specific inhibitor, AG490, the paracrine neuroprotective and pro-angiogenic effects of ahNSCs were reversed. This pre-clinical study that closely simulated clinical settings and provided treatment mechanisms of ahNSCs for ischemic stroke may aid the development of protocols for subsequent clinical trials of ahNSCs and the realization of clinically available stem cell therapeutics for ischemic stroke.


Subject(s)
Ischemic Stroke , Neural Stem Cells , Neuroprotective Agents , Stroke , Animals , Humans , Rats , Angiogenesis Inducing Agents , Disease Models, Animal , Infarction, Middle Cerebral Artery/drug therapy , Ischemic Stroke/therapy , Janus Kinase 2/metabolism , Models, Animal , Neural Stem Cells/metabolism , Neuroprotective Agents/pharmacology , Neuroprotective Agents/therapeutic use , STAT3 Transcription Factor/metabolism , Stroke/drug therapy
3.
Anticancer Res ; 41(7): 3349-3361, 2021 Jul.
Article in English | MEDLINE | ID: mdl-34230131

ABSTRACT

BACKGROUND/AIM: The present study investigated the oncogenic functions of TACC3 in the progression of gastric cancer (GC). MATERIALS AND METHODS: We analysed TACC3 in relation to cell growth, invasion capability, expression of epithelial-mesenchymal transition (EMT)-related markers, and ERK/Akt/cyclin D1 signaling factors. The correlation between the immunohistochemically confirmed expression of TACC3 and clinical factors was also analyzed. RESULTS: The increased proliferation and invasion of TACC3-over-expressing GC cells was accompanied by altered regulation of EMT-associated markers and activation of ERK/Akt/cyclin D1 signaling. Immunohistochemical analysis of TACC3 in human GC tissues revealed that its expression is correlated with aggressive characteristics and poor prognosis of intestinal-type GC. CONCLUSION: TACC3 contributes to gastric tumorigenesis by promoting EMT via the ERK/Akt/cyclin D1 signaling pathway. The correlation between TACC3 expression and multiple clinicopathological variables implies that its effective therapeutic targeting in GC will depend on the tumor subtype.


Subject(s)
Carcinogenesis/genetics , Cyclin D1/genetics , Epithelial-Mesenchymal Transition/genetics , MAP Kinase Signaling System/genetics , Microtubule-Associated Proteins/genetics , Proto-Oncogene Proteins c-akt/genetics , Stomach Neoplasms/genetics , Carcinogenesis/pathology , Cell Line, Tumor , Cell Movement/genetics , Cell Proliferation/genetics , Gene Expression Regulation, Neoplastic/genetics , Humans , Neoplasm Invasiveness/genetics , Neoplasm Invasiveness/pathology , Signal Transduction/genetics , Stomach/pathology , Stomach Neoplasms/pathology
4.
BMB Rep ; 53(10): 539-544, 2020 Nov.
Article in English | MEDLINE | ID: mdl-32843132

ABSTRACT

Skin aging appears to be the result of overlapping intrinsic (including genetic and hormonal factors) and extrinsic (external environment including chronic light exposure, chemicals, and toxins) processes. These factors cause decreases in the synthesis of collagen type I and elastin in fibroblasts and increases in the melanin in melanocytes. Collagen Type I is the most abundant type of collagen and is a major structural protein in human body tissues. In previous studies, many products containing collagen derived from land and marine animals as well as other sources have been used for a wide range of purposes in cosmetics and food. However, to our knowledge, the effects of human collagenderived peptides on improvements in skin condition have not been investigated. Here we isolate and identify the domain of a human COL1A2-derived protein which promotes fibroblast cell proliferation and collagen type I synthesis. This human COL 1A2-derived peptide enhances wound healing and elastin production. Finally, the human collagen alpha-2 type I-derived peptide (SMM) ameliorates collagen type I synthesis, cell proliferation, cell migration, and elastin synthesis, supporting a significant anti-wrinkle effect. Collectively, these results demonstrate that human collagen alpha-2 type I-derived peptides is practically accessible in both cosmetics and food, with the goal of improving skin condition. [BMB Reports 2020; 53(10): 539-544].


Subject(s)
Collagen Type I/metabolism , Fibroblasts/metabolism , Skin/metabolism , Cell Movement/drug effects , Cell Proliferation/drug effects , Cells, Cultured , Collagen/biosynthesis , Collagen/metabolism , Collagen Type I/physiology , Elastin/biosynthesis , Elastin/metabolism , Elastin/pharmacology , Humans , Skin Aging/physiology , Wound Healing/physiology
5.
Nucleic Acids Res ; 47(12): 6299-6314, 2019 07 09.
Article in English | MEDLINE | ID: mdl-31045206

ABSTRACT

Histone H2AX undergoes a phosphorylation switch from pTyr142 (H2AX-pY142) to pSer139 (γH2AX) in the DNA damage response (DDR); however, the functional role of H2AX-pY142 remains elusive. Here, we report a new layer of regulation involving transcription-coupled H2AX-pY142 in the DDR. We found that constitutive H2AX-pY142 generated by Williams-Beuren syndrome transcription factor (WSTF) interacts with RNA polymerase II (RNAPII) and is associated with RNAPII-mediated active transcription in proliferating cells. Also, removal of pre-existing H2AX-pY142 by ATM-dependent EYA1/3 phosphatases disrupts this association and requires for transcriptional silencing at transcribed active damage sites. The following recovery of H2AX-pY142 via translocation of WSTF to DNA lesions facilitates transcription-coupled homologous recombination (TC-HR) in the G1 phase, whereby RAD51 loading, but not RPA32, utilizes RNAPII-dependent active RNA transcripts as donor templates. We propose that the WSTF-H2AX-RNAPII axis regulates transcription and TC-HR repair to maintain genome integrity.


Subject(s)
Histones/metabolism , Recombinational DNA Repair , Transcription Factors/metabolism , Transcription, Genetic , Cell Line, Tumor , DNA-Binding Proteins/metabolism , G1 Phase/genetics , HEK293 Cells , HeLa Cells , Histones/chemistry , Humans , Intracellular Signaling Peptides and Proteins/metabolism , Nuclear Proteins/metabolism , Phosphorylation , Protein Tyrosine Phosphatases/metabolism , RNA Polymerase II/metabolism , Tyrosine/metabolism
6.
Nat Commun ; 10(1): 1577, 2019 04 05.
Article in English | MEDLINE | ID: mdl-30952868

ABSTRACT

DNA double-strand break (DSB) signaling and repair are critical for genome integrity. They rely on highly coordinated processes including posttranslational modifications of proteins. Here we show that Pellino1 (Peli1) is a DSB-responsive ubiquitin ligase required for the accumulation of DNA damage response proteins and efficient homologous recombination (HR) repair. Peli1 is activated by ATM-mediated phosphorylation. It is recruited to DSB sites in ATM- and γH2AX-dependent manners. Interaction of Peli1 with phosphorylated histone H2AX enables it to bind to and mediate the formation of K63-linked ubiquitination of NBS1, which subsequently results in feedback activation of ATM and promotes HR repair. Collectively, these results provide a DSB-responsive factor underlying the connection between ATM kinase and DSB-induced ubiquitination.


Subject(s)
Ataxia Telangiectasia Mutated Proteins/metabolism , Cell Cycle Proteins/metabolism , DNA Repair , Nuclear Proteins/metabolism , Nuclear Proteins/physiology , Ubiquitin-Protein Ligases/physiology , Ataxia Telangiectasia Mutated Proteins/physiology , Cell Line, Tumor , DNA Breaks, Double-Stranded , Humans , Nuclear Proteins/genetics , Ubiquitin-Protein Ligases/genetics , Ubiquitin-Protein Ligases/metabolism , Ubiquitination
7.
Exp Mol Med ; 50(10): 1-12, 2018 10 22.
Article in English | MEDLINE | ID: mdl-30367032

ABSTRACT

The brain-expressed X-linked 4 (BEX4) gene has been recently identified as a mediator of microtubule hyperacetylation through sirtuin 2 inhibition and is highly overexpressed in human cancers. However, the gain-of-function molecular mechanism of the BEX4 gene in human cancers still needs to be elucidated. This study shows that BEX4 colocalizes and interacts with Polo-like kinase 1 (PLK1) at centrosomes, spindle poles, and midbodies, particularly during mitosis. Interestingly, PLK1-mediated phosphorylation upregulates the stability of BEX4 protein, and the PLK1-BEX4 interaction allows abnormal mitotic cells to adapt to aneuploidy rather than undergo apoptotic cell death. In summary, these results suggest that the oncogenicity of BEX4 is conferred by PLK1-mediated phosphorylation, and thus, the BEX4-PLK1 interaction is a novel oncogenic signal that enables the acquisition of chromosomal aneuploidy.


Subject(s)
Cell Cycle Proteins/metabolism , Microtubule-Associated Proteins/genetics , Oncogene Proteins/genetics , Protein Serine-Threonine Kinases/metabolism , Proto-Oncogene Proteins/metabolism , Aneuploidy , Animals , Apoptosis/genetics , Cell Cycle , Gene Expression Regulation , HEK293 Cells , HeLa Cells , Humans , Microtubule-Associated Proteins/metabolism , Mitosis/genetics , Oncogene Proteins/metabolism , Phosphorylation , Polo-Like Kinase 1
8.
Anticancer Res ; 38(3): 1303-1310, 2018 03.
Article in English | MEDLINE | ID: mdl-29491053

ABSTRACT

BACKGROUND/AIM: Breast cancer is the most common malignant cancer type in women, and triple-negative breast cancer (TNBC) is an extremely aggressive subtype of breast cancer with poor prognosis rates. The present study investigated the antitumor effect of polo-like kinase 1 (PLK1) inhibitor in combination with the tankyrase-1 (TNKS1) inhibitor on TNBC cells. MATERIALS AND METHODS: We evaluated the antitumor effects of combination therapy with PLK1 and TNKS1 inhibitor using cell viability analysis, apoptosis assay and transwell assay for cell invasion and migration in TNBC cells. RESULTS: Combination treatment with PLK1 and TNKS1 inhibitors not only inhibited the invasion and migration capacity of TNBC cells, but also increased the apoptosis and cell death of TNBC cells. The viability of TNBC cells with low expression of ß-catenin and high expression of PLK1 was not affected by treatment with PLK1 inhibitor. However, the combination treatment with the TNKS1 inhibitor significantly decreased cell invasion and migration and increased apoptosis. CONCLUSION: Combination therapy of PLK1 and TNKS1 inhibitors may improve the therapeutic efficacy of the current treatment for TNBC.


Subject(s)
Cell Cycle Proteins/antagonists & inhibitors , Enzyme Inhibitors/therapeutic use , Protein Serine-Threonine Kinases/antagonists & inhibitors , Proto-Oncogene Proteins/antagonists & inhibitors , Tankyrases/antagonists & inhibitors , Triple Negative Breast Neoplasms/drug therapy , Apoptosis/drug effects , Apoptosis/genetics , Cell Cycle Proteins/genetics , Cell Cycle Proteins/metabolism , Cell Line, Tumor , Cell Movement/drug effects , Cell Movement/genetics , Cell Survival/drug effects , Cell Survival/genetics , Drug Synergism , Drug Therapy, Combination , Enzyme Inhibitors/pharmacology , Female , HeLa Cells , Humans , Kaplan-Meier Estimate , MCF-7 Cells , Protein Serine-Threonine Kinases/genetics , Protein Serine-Threonine Kinases/metabolism , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins/metabolism , RNA Interference , Tankyrases/genetics , Tankyrases/metabolism , Triple Negative Breast Neoplasms/genetics , Triple Negative Breast Neoplasms/metabolism , Polo-Like Kinase 1
9.
Biochem Biophys Res Commun ; 496(2): 633-640, 2018 02 05.
Article in English | MEDLINE | ID: mdl-29355525

ABSTRACT

In spite of the push to identify modifiers of BRCAness, it still remains unclear how tumor suppressor BRCA1 is lost in breast cancers in the absence of genetic or epigenetic aberrations. Mounting evidence indicates that the transforming acidic coiled-coil 3 (TACC3) plays an important role in the centrosome-microtubule network during mitosis and gene expression, and that deregulation of TACC3 is associated with breast cancer. However, the molecular mechanisms by which TACC3 contributes to breast cancer development have yet to be elucidated. Herein, we found that high levels of TACC3 in human mammary epithelial cells can cause genomic instability possibly in part through destabilizing BRCA1. We also found that high levels of TACC3 inhibited the interaction between BRCA1 and BARD1, thus subsequently allowing the BARD1-uncoupled BRCA1 to be destabilized by ubiquitin-mediated proteosomal pathway. Moreover, there is an inverse correlation between TACC3 and BRCA1 expression in breast cancer tissues. Overall, our findings provide a new insight into the role of TACC3 in genomic instability and breast tumorigenesis.


Subject(s)
BRCA1 Protein/metabolism , Microtubule-Associated Proteins/metabolism , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Cell Line , Female , Genomic Instability , Humans , Protein Interaction Maps , Protein Stability , Proteolysis , Tumor Suppressor Proteins/metabolism , Ubiquitin-Protein Ligases/metabolism , Ubiquitination
10.
Oncotarget ; 8(49): 86799-86815, 2017 Oct 17.
Article in English | MEDLINE | ID: mdl-29156836

ABSTRACT

BRCA1 is an important player in the DNA damage response signaling, and its deficiency results in genomic instability. A complete loss or significantly reduced BRCA1 protein expression is often found in sporadic breast cancer cases despite the absence of genetic or epigenetic aberrations, suggesting the existence of other regulatory mechanisms controlling BRCA1 protein expression. Herein, we demonstrate that Fyn-related kinase (Frk)/Rak plays an important role in maintaining genomic stability, possibly in part through positively regulating BRCA1 protein stability and function via tyrosine phosphorylation on BRCA1 Tyr1552. In addition, Rak deficiency confers cellular sensitivity to DNA damaging agents and poly(ADP-ribose) polymerase (PARP) inhibitors. Overall, our findings highlight a critical role of Rak in the maintenance of genomic stability, at least in part, through protecting BRCA1 and provide novel treatment strategies for patients with breast tumors lacking Rak.

11.
Cell Death Differ ; 24(3): 469-480, 2017 03.
Article in English | MEDLINE | ID: mdl-28009353

ABSTRACT

Pellino-1 is an E3 ubiquitin ligase acting as a critical mediator for a variety of immune receptor signaling pathways, including Toll-like receptors, interleukin-1 receptor and T-cell receptors. We recently showed that the Pellino-1-transgenic (Tg) mice developed multiple tumors with different subtypes in hematolymphoid and solid organs. However, the molecular mechanism underlying the oncogenic role of Pellino-1 in solid tumors remains unknown. Pellino-1-Tg mice developed adenocarcinoma in the lungs, and Pellino-1 expression was higher in human lung adenocarcinoma cell lines compared with non-neoplastic bronchial epithelial cell lines. Pellino-1 overexpression increased the cell proliferation, survival, colony formation, invasion and migration of lung adenocarcinoma cells, whereas Pellino-1 knock-down showed the opposite effect. Pellino-1 overexpression activated PI3K/Akt and ERK signaling pathways and elicited an epithelial-mesenchymal transition (EMT) phenotype of lung adenocarcinoma cells. Pellino-1-mediated EMT was demonstrated through morphology, the upregulation of Vimentin, Slug and Snail expression and the downregulation of E-cadherin and ß-catenin expression. Notably, Pellino-1 had a direct effect on the overexpression of Snail and Slug through Lys63-mediated polyubiquitination and the subsequent stabilization of these proteins. Pellino-1 expression level was significantly correlated with Snail and Slug expression in human lung adenocarcinoma tissues, and lung tumors from Pellino-1-Tg mice showed Snail and Slug overexpression. The Pellino-1-mediated increase in the migration of lung adenocarcinoma cells was mediated by Snail and Slug expression. Taken together, these results show that Pellino-1 contributes to lung tumorigenesis by inducing overexpression of Snail and Slug and promoting EMT. Pellino-1 might be a potential therapeutic target for lung cancer.


Subject(s)
Lung Neoplasms/pathology , Nuclear Proteins/metabolism , Snail Family Transcription Factors/metabolism , Ubiquitin-Protein Ligases/metabolism , A549 Cells , Animals , Cell Line, Tumor , Chromones/pharmacology , Down-Regulation/drug effects , Epithelial-Mesenchymal Transition , Flavonoids/pharmacology , Glycogen Synthase Kinase 3 beta/genetics , Glycogen Synthase Kinase 3 beta/metabolism , Humans , Lung Neoplasms/metabolism , Mice , Mice, Nude , Mice, Transgenic , Morpholines/pharmacology , Nuclear Proteins/antagonists & inhibitors , Nuclear Proteins/genetics , Phosphatidylinositol 3-Kinases/metabolism , Phosphoinositide-3 Kinase Inhibitors , Proto-Oncogene Proteins c-akt/metabolism , Signal Transduction , Snail Family Transcription Factors/antagonists & inhibitors , Snail Family Transcription Factors/genetics , Ubiquitin-Protein Ligases/antagonists & inhibitors , Ubiquitin-Protein Ligases/genetics , Ubiquitination
12.
Cell Death Dis ; 7(8): e2336, 2016 08 11.
Article in English | MEDLINE | ID: mdl-27512957

ABSTRACT

Five brain-expressed X-linked (BEX) gene members (BEX1-5) are arranged in tandem on chromosome X, and are highly conserved across diverse species. However, little is known about the function and role of BEX. This study represents a first attempt to demonstrate the molecular details of a novel oncogene BEX4. Among BEX proteins, BEX4 localizes to microtubules and spindle poles, and interacts with α-tubulin (α-TUB) and sirtuin 2 (SIRT2). The overexpression of BEX4 leads to the hyperacetylation of α-TUB by inhibiting SIRT2-mediated deacetylation. Furthermore, we found BEX4 expression conferred resistance to apoptotic cell death but led to acquisition of aneuploidy, and also increased the proliferating potential and growth of tumors. These results suggest that BEX4 overexpression causes an imbalance between TUB acetylation and deacetylation by SIRT2 inhibition and induces oncogenic aneuploidy transformation.


Subject(s)
Microtubule-Associated Proteins/metabolism , Microtubules/metabolism , Neoplasms/metabolism , Oncogene Proteins/metabolism , Proteins/metabolism , Sirtuin 2/metabolism , Acetylation , Aneuploidy , Animals , Cell Proliferation , HeLa Cells , Humans , Male , Mice, Nude , Mitosis , Neoplasms/pathology , Protein Binding , Tubulin/metabolism
13.
Oncotarget ; 7(27): 41811-41824, 2016 Jul 05.
Article in English | MEDLINE | ID: mdl-27248820

ABSTRACT

Pellino-1 is an E3 ubiquitin ligase that mediates immune receptor signaling pathways. The role of Pellino-1 in oncogenesis of lung cancer was investigated in this study. Pellino-1 expression was increased in human lung cancer cell lines compared with non-neoplastic lung cell lines. Pellino-1 overexpression in human lung cancer cells, A549 and H1299 cells, increased the survival and colony forming ability. Pellino-1 overexpression in these cells also conferred resistance to cisplatin- or paclitaxel-induced apoptosis. In contrast, depletion of Pellino-1 decreased the survival of A549 and H1299 cells and sensitized these cells to cisplatin- and paclitaxel-induced apoptosis. Pellino-1 overexpression in A549 and H1299 cells upregulated the expression of inhibitor of apoptosis (IAP) proteins, including cIAP1 and cIAP2, while Pellino-1 depletion downregulated these molecules. Notably, Pellino-1 directly interacted with cIAP2 and stabilized cIAP2 through lysine63-mediated polyubiquitination via its E3 ligase activity. Pellino-1-mediated chemoresistance in lung cancer cells was dependent on the induction of cIAP2. Moreover, a strong positive correlation between Pellino-1 and the cIAP2 expression was observed in human lung adenocarcinoma tissues. Taken together, these results demonstrate that Pellino-1 contributes to lung oncogenesis through the overexpression of cIAP2 and promotion of cell survival and chemoresistance. Pellino-1 might be a novel oncogene and potential therapeutic target in lung cancer.


Subject(s)
Baculoviral IAP Repeat-Containing 3 Protein/metabolism , Lung Neoplasms/metabolism , Nuclear Proteins/metabolism , Polyubiquitin/metabolism , Ubiquitin-Protein Ligases/metabolism , A549 Cells , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Apoptosis/genetics , Baculoviral IAP Repeat-Containing 3 Protein/genetics , Cell Line , Cell Line, Tumor , Cell Survival/drug effects , Cell Survival/genetics , Cisplatin/pharmacology , Drug Resistance, Neoplasm/genetics , HCT116 Cells , HEK293 Cells , Humans , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Lysine/genetics , Lysine/metabolism , Nuclear Proteins/genetics , Paclitaxel/pharmacology , RNA Interference , Ubiquitin-Protein Ligases/genetics , Ubiquitination , Up-Regulation
14.
J Clin Invest ; 124(11): 4976-88, 2014 Nov.
Article in English | MEDLINE | ID: mdl-25295537

ABSTRACT

The signal-responsive E3 ubiquitin ligase pellino 1 (PELI1) regulates TLR and T cell receptor (TCR) signaling and contributes to the maintenance of autoimmunity; however, little is known about the consequence of mutations that result in upregulation of PELI1. Here, we developed transgenic mice that constitutively express human PELI1 and determined that these mice have a shorter lifespan due to tumor formation. Constitutive expression of PELI1 resulted in ligand-independent hyperactivation of B cells and facilitated the development of a wide range of lymphoid tumors, with prominent B cell infiltration observed across multiple organs. PELI1 directly interacted with the oncoprotein B cell chronic lymphocytic leukemia (BCL6) and induced lysine 63-mediated BCL6 polyubiquitination. In samples from patients with diffuse large B cell lymphomas (DLBCLs), PELI1 expression levels positively correlated with BCL6 expression, and PELI1 overexpression was closely associated with poor prognosis in DLBCLs. Together, these results suggest that increased PELI1 expression and subsequent induction of BCL6 promotes lymphomagenesis and that this pathway may be a potential target for therapeutic strategies to treat B cell lymphomas.


Subject(s)
DNA-Binding Proteins/metabolism , Lymphoma, Large B-Cell, Diffuse/metabolism , Nuclear Proteins/physiology , Polyubiquitin/metabolism , Ubiquitin-Protein Ligases/physiology , Ubiquitination , Animals , Carcinogenesis/metabolism , Cell Line, Tumor , Humans , Kaplan-Meier Estimate , Lymphangiogenesis , Lymphoma, Large B-Cell, Diffuse/mortality , Mice, Inbred C57BL , Mice, Transgenic , Prognosis , Proportional Hazards Models , Protein Stability , Proto-Oncogene Proteins c-bcl-6 , ROC Curve
15.
PLoS One ; 8(8): e70353, 2013.
Article in English | MEDLINE | ID: mdl-23936413

ABSTRACT

The third member of transforming acidic coiled-coil protein (TACC) family, TACC3, has been shown to be an important player in the regulation of centrosome/microtubule dynamics during mitosis and found to be deregulated in a variety of human malignancies. Our previous studies have suggested that TACC3 may be involved in cervical cancer progression and chemoresistance, and its overexpression can induce epithelial-mesenchymal transition (EMT) by activating the phosphatidylinositol 3-kinase (PI3K)/Akt and extracellular signal-regulated protein kinases (ERKs) signal transduction pathways. However, the upstream mechanisms of TACC3-mediated EMT and its functional/clinical importance in human cervical cancer remain elusive. Epidermal growth factor (EGF) has been shown to be a potent inducer of EMT in cervical cancer and associated with tumor invasion and metastasis. In this study, we found that TACC3 is overexpressed in cervical cancer and can be induced upon EGF stimulation. The induction of TACC3 by EGF is dependent on the tyrosine kinase activity of the EGF receptor (EGFR). Intriguingly, depletion of TACC3 abolishes EGF-mediated EMT, suggesting that TACC3 is required for EGF/EGFR-driven EMT process. Moreover, Snail, a key player in EGF-mediated EMT, is found to be correlated with the expression of TACC3 in cervical cancer. Collectively, our study highlights a novel function for TACC3 in EGF-mediated EMT process and suggests that targeting of TACC3 may be an attractive strategy to treat cervical cancers driven by EGF/EGFR signaling pathways.


Subject(s)
Epidermal Growth Factor/pharmacology , Epithelial-Mesenchymal Transition/drug effects , Microtubule-Associated Proteins/metabolism , Uterine Cervical Neoplasms/metabolism , Uterine Cervical Neoplasms/pathology , Cell Line, Tumor , ErbB Receptors/metabolism , Female , Gene Expression Regulation, Neoplastic/drug effects , Humans , Microtubule-Associated Proteins/genetics , Middle Aged , Snail Family Transcription Factors , Transcription Factors/metabolism , Uterine Cervical Neoplasms/genetics
16.
Cancer Lett ; 336(1): 24-33, 2013 Aug 09.
Article in English | MEDLINE | ID: mdl-23624299

ABSTRACT

Fine-tuned regulation of the centrosome/microtubule dynamics during mitosis is essential for faithful cell division. Thus, it is not surprising that deregulations in this dynamic network can contribute to genomic instability and tumorigenesis. Indeed, centrosome loss or amplification, spindle multipolarity and aneuploidy are often found in a majority of human malignancies, suggesting that defects in centrosome and associated microtubules may be directly or indirectly linked to cancer. Therefore, future research to identify and characterize genes required for the normal centrosome function and microtubule dynamics may help us gain insight into the complexity of cancer, and further provide new avenues for prognostic, diagnostics and therapeutic interventions. Members of the transforming acidic coiled-coil proteins (TACCs) family are emerging as important players of centrosome and microtubule-associated functions. Growing evidence indicates that TACCs are involved in the progression of certain solid tumors. Here, we will discuss our current understanding of the biological function of TACCs, their relevance to human cancer and possible implications for cancer management.


Subject(s)
Gene Expression Regulation, Neoplastic , Microtubule-Associated Proteins/metabolism , Neoplasms/genetics , Animals , Carrier Proteins/metabolism , Cell Transformation, Neoplastic , Centrosome/ultrastructure , Fetal Proteins/metabolism , Gene Expression Profiling , Humans , Microtubules/ultrastructure , Neoplasms/metabolism , Neoplasms/pathology , Nuclear Proteins/metabolism , Oncogenes , Tumor Suppressor Proteins/metabolism
17.
Cancer Lett ; 332(1): 63-73, 2013 May 10.
Article in English | MEDLINE | ID: mdl-23348690

ABSTRACT

Transforming acidic coiled-coil protein 3 (TACC3) is a member of the TACC family, essential for mitotic spindle dynamics and centrosome integrity during mitosis. Mounting evidence suggests that deregulation of TACC3 is associated with various types of human cancer. However, the molecular mechanisms by which TACC3 contributes to the development of cancer remain largely unknown. Here, we propose a novel mechanism by which TACC3 regulates epithelial-mesenchymal transition (EMT). By modulating the expression of TACC3, we found that overexpression of TACC3 leads to changes in cell morphology, proliferation, transforming capability, migratory/invasive behavior as well as the expression of EMT-related markers. Moreover, phosphatidylinositol 3-kinase (PI3K)/Akt and extracellular signal-regulated protein kinases (ERKs) signaling pathways are critical for TACC3-mediated EMT process. Notably, depletion of TACC3 is sufficient to suppress EMT phenotype. Collectively, our findings identify TACC3 as a driver of tumorigenesis as well as an inducer of oncogenic EMT and highlight its overexpression as a potential therapeutic target for preventing EMT-associated tumor progression and invasion.


Subject(s)
Epithelial-Mesenchymal Transition , Extracellular Signal-Regulated MAP Kinases/metabolism , Microtubule-Associated Proteins/metabolism , Phosphatidylinositol 3-Kinase/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Signal Transduction , Cell Movement , Cell Proliferation , Cell Shape , Cell Transformation, Neoplastic/metabolism , Cell Transformation, Neoplastic/pathology , Enzyme Activation , Epithelial-Mesenchymal Transition/drug effects , Extracellular Signal-Regulated MAP Kinases/antagonists & inhibitors , Extracellular Signal-Regulated MAP Kinases/genetics , HEK293 Cells , HeLa Cells , Humans , Microtubule-Associated Proteins/genetics , Neoplasm Invasiveness , Phosphoinositide-3 Kinase Inhibitors , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins c-akt/antagonists & inhibitors , Proto-Oncogene Proteins c-akt/genetics , RNA Interference , Signal Transduction/drug effects , Time Factors , Transfection , beta Catenin/metabolism
18.
Cell Cycle ; 12(3): 442-51, 2013 Feb 01.
Article in English | MEDLINE | ID: mdl-23324348

ABSTRACT

Multipotent mesenchymal stem/stromal cells (MSCs) are capable of differentiating into a variety of cell types from different germ layers. However, the molecular and biochemical mechanisms underlying the transdifferentiation of MSCs into specific cell types still need to be elucidated. In this study, we unexpectedly found that treatment of human adipose- and bone marrow-derived MSCs with cyclin-dependent kinase (CDK) inhibitor, in particular CDK4 inhibitor, selectively led to transdifferentiation into neural cells with a high frequency. Specifically, targeted inhibition of CDK4 expression using recombinant adenovial shRNA induced the neural transdifferentiation of human MSCs. However, the inhibition of CDK4 activity attenuated the syngenic differentiation of human adipose-derived MSCs. Importantly, the forced regulation of CDK4 activity showed reciprocal reversibility between neural differentiation and dedifferentiation of human MSCs. Together, these results provide novel molecular evidence underlying the neural transdifferentiation of human MSCs; in addition, CDK4 signaling appears to act as a molecular switch from syngenic differentiation to neural transdifferentiation of human MSCs.


Subject(s)
Cell Differentiation , Cell Transdifferentiation , Cyclin-Dependent Kinase 4/metabolism , Mesenchymal Stem Cells/metabolism , Neurons/metabolism , Adipose Tissue/cytology , Aurora Kinases , Bone Marrow Cells/cytology , CDC2 Protein Kinase/antagonists & inhibitors , Cell Cycle/drug effects , Cell Cycle Proteins/antagonists & inhibitors , Cell Differentiation/drug effects , Cell Differentiation/genetics , Cell Transdifferentiation/drug effects , Cell Transdifferentiation/genetics , Cells, Cultured , Cyclin-Dependent Kinase 2/antagonists & inhibitors , Cyclin-Dependent Kinase 4/antagonists & inhibitors , Cyclin-Dependent Kinase 4/genetics , Glycogen Synthase Kinase 3/antagonists & inhibitors , Glycogen Synthase Kinase 3 beta , Humans , MAP Kinase Kinase 1/antagonists & inhibitors , Protein Serine-Threonine Kinases/antagonists & inhibitors , Proto-Oncogene Proteins/antagonists & inhibitors , RNA Interference , RNA, Small Interfering , Signal Transduction , Polo-Like Kinase 1
19.
Biochem Res Int ; 2012: 195903, 2012.
Article in English | MEDLINE | ID: mdl-22852086

ABSTRACT

Mitosis is tightly regulated and any errors in this process often lead to aneuploidy, genomic instability, and tumorigenesis. Deregulation of mitotic kinases is significantly associated with improper cell division and aneuploidy. Because of their importance during mitosis and the relevance to cancer, mitotic kinase signaling has been extensively studied over the past few decades and, as a result, several mitotic kinase inhibitors have been developed. Despite promising preclinical results, targeting mitotic kinases for cancer therapy faces numerous challenges, including safety and patient selection issues. Therefore, there is an urgent need to better understand the molecular mechanisms underlying mitotic kinase signaling and its interactive network. Increasing evidence suggests that tumor suppressor p53 functions at the center of the mitotic kinase signaling network. In response to mitotic spindle damage, multiple mitotic kinases phosphorylate p53 to either activate or deactivate p53-mediated signaling. p53 can also regulate the expression and function of mitotic kinases, suggesting the existence of a network of mutual regulation, which can be positive or negative, between mitotic kinases and p53 signaling. Therefore, deciphering this regulatory network will provide knowledge to overcome current limitations of targeting mitotic kinases and further improve the results of targeted therapy.

20.
EMBO J ; 29(20): 3544-57, 2010 Oct 20.
Article in English | MEDLINE | ID: mdl-20818333

ABSTRACT

Cohesin is a multiprotein complex that establishes sister chromatid cohesion from S phase until mitosis or meiosis. In vertebrates, sister chromatid cohesion is dissolved in a stepwise manner: most cohesins are removed from the chromosome arms via a process that requires polo-like kinase 1 (Plk1), aurora B and Wapl, whereas a minor amount of cohesin, found preferentially at the centromere, is cleaved by separase following its activation by the anaphase-promoting complex/cyclosome. Here, we report that our budding yeast two-hybrid assay identified hsSsu72 phosphatase as a Rad21-binding protein. Additional experiments revealed that Ssu72 directly interacts with Rad21 and SA2 in vitro and in vivo, and associates with sister chromatids in human cells. Interestingly, depletion or mutational inactivation of Ssu72 phosphatase activity caused the premature resolution of sister chromatid arm cohesion, whereas the overexpression of Ssu72 yielded high resistance to this resolution. Interestingly, it appears that Ssu72 regulates the cohesion of chromosome arms but not centromeres, and acts by counteracting the phosphorylation of SA2. Thus, our study provides important new evidence, suggesting that Ssu72 is a novel cohesin-binding protein capable of regulating cohesion between sister chromatid arms.


Subject(s)
Carrier Proteins/metabolism , Cell Cycle Proteins/metabolism , Chromatids/metabolism , Chromosomal Proteins, Non-Histone/metabolism , Chromosome Segregation , Amino Acid Sequence , Animals , Carrier Proteins/genetics , Cell Cycle Proteins/genetics , Chromatin/metabolism , Chromosomal Proteins, Non-Histone/genetics , DNA-Binding Proteins , HeLa Cells , Humans , Molecular Sequence Data , Nuclear Proteins/genetics , Nuclear Proteins/metabolism , Phosphoprotein Phosphatases , Phosphoproteins/genetics , Phosphoproteins/metabolism , Protein Binding , Recombinant Fusion Proteins/genetics , Recombinant Fusion Proteins/metabolism , Two-Hybrid System Techniques , Cohesins
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