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Ce Li, Lutao Du, Yidan Ren, Xiaoyan Liu, Qinlian Jiao, Donghai Cui, Mingxin Wen, Chuanxin Wang, Guangwei Wei, Yunshan Wang, Aiguo Ji, Qin Wang
BACKGROUND: S-phase kinase-associated protein 2 (SKP2) is an oncogene and cell cycle regulator that specifically recognizes phosphorylated cell cycle regulator proteins and mediates their ubiquitination. Programmed cell death protein 4 (PDCD4) is a tumor suppressor gene that plays a role in cell apoptosis and DNA-damage response via interacting with eukaryotic initiation factor-4A (eIF4A) and P53. Previous research showed SKP2 may interact with PDCD4, however the relationship between SKP2 and PDCD4 is unclear...
February 13, 2019: Journal of Experimental & Clinical Cancer Research: CR
Guihua Wang, Jie Long, Yuan Gao, Weina Zhang, Fei Han, Chuan Xu, Li Sun, Shun-Chin Yang, Jingqin Lan, Zhenlin Hou, Zhen Cai, Guoxiang Jin, Che-Chia Hsu, Yu-Hui Wang, Junbo Hu, Tsai-Yu Chen, Hongyu Li, Min Gyu Lee, Hui-Kuan Lin
The serine/threonine kinase Akt plays a central role in cell proliferation, survival and metabolism, and its hyperactivation is linked to cancer progression. Here we report that Akt undergoes K64 methylation by SETDB1, which is crucial for cell membrane recruitment, phosphorylation and activation of Akt following growth factor stimulation. Furthermore, we reveal an adaptor function of histone demethylase JMJD2A, which is important for recognizing Akt K64 methylation and recruits E3 ligase TRAF6 and Skp2-SCF to the Akt complex, independently of its demethylase activity, thereby initiating K63-linked ubiquitination, cell membrane recruitment and activation of Akt...
January 28, 2019: Nature Cell Biology
Xiuhua Fan, Yan Wang, Jiajia Fan, Rui Chen
SMAD ubiquitination regulatory factor 1 (SMURF1) has been described as a tumor suppressor in multiple aggressive cancers. Nevertheless, the potential role of SMURF1 in ovarian cancer invasion and epithelial-to-mesenchymal transition (EMT) remains unclear. The aim of this study was to evaluate the efficacy of SMURF1 on tumor migration and EMT and elucidate the underlying molecular mechanism in ovarian carcinoma. We found elevated SMURF1 in several ovarian cancer cells in both messenger RNA and protein. Additionally, silencing SMURF1 apparently repressed cell proliferation and invasion capacity of SKOV3 and A2780 cells and markedly attenuated expression of linked proteins such as proliferating cellnuclear antigen, matrix metalloproteinase (MMP)-2, and MMP-9...
January 22, 2019: Journal of Cellular Biochemistry
Sung Hyun Kim, Myoung-Ok Kim, Ki-Rim Kim
Background: Human hepatocellular carcinoma (HCC) is a common liver tumor and the main cause of cancer-related death. Tyrosine kinase inhibitors, such as imatinib and GNF5 which were developed to treat chronic myelogenous leukemia, regulate the progression of various cancers. The aim of this study was to confirm the anti-tumor activity of tyrosine kinase inhibitors through regulation of S-phase kinase-associated protein 2 (Skp2), an important oncogenic factor in various cancer cells, in human hepatocarcinoma SK-HEP1 cells...
December 2018: Journal of Cancer Prevention
Yutaka Koyama, Satoshi Sumie, Yasutaka Nakano, Tomoya Nagao, Shiho Tokumaru, Shotaro Michinaga
Brain injury-mediated induction of reactive astrocytes often leads to glial scar formation in damaged brain regions. Activation of signal transducer and activator of transcription 3 (STAT3), a member of the STAT family of transcription factors, plays a pivotal role in inducing reactive astrocytes and glial scar formation. Endothelin-1 (ET-1) is a vasoconstrictor peptide and its levels increase in brain disorders and promote astrocytic proliferation through ETB receptors. To clarify the mechanisms underlying ET-1-mediated astrocytic proliferation, here we examined its effects on STAT3 in cultured rat astrocytes...
January 22, 2019: Journal of Biological Chemistry
Zhengke Li, Dong-Lai Qi, Hardeep Pal Singh, Yue Zou, Binghui Shen, David Cobrinik
Retinoblastoma is a childhood retinal tumor that develops from cone photoreceptor precursors in response to inactivating RB1 mutations and loss of functional RB protein. The cone precursor's response to RB loss involves cell-type-specific signaling circuitry that helps to drive tumorigenesis. One component of the cone precursor circuitry, the thyroid hormone receptor β2 (TRβ2), enables the aberrant proliferation of diverse RB-deficient cells in part by opposing the down-regulation of S-phase kinase-associated protein (SKP2) by the more widely expressed and tumor suppressive TRβ1...
January 14, 2019: Journal of Biological Chemistry
Zongzhe Jiang, Bowen Xing, Zijie Feng, Jian Ma, Xiaosong Ma, Xianxin Hua
OBJECTIVES: Menin, a chromatin binding protein, interacts with various epigenetic regulators to regulate gene transcription, whereas forkhead box protein O1 (FOXO1) is a transcription factor that can be regulated by multiple signaling pathways. Both menin and FOXO1 are crucial regulators of β-cell function and metabolism; however, whether or how they interplay to regulate β cells is not clear. METHODS: To examine whether menin affects expression of FOXO1, we ectopically expressed menin complementary DNA and small hairpin RNA targeting menin via a retroviral vector in INS-1 cells...
February 2019: Pancreas
Yehui Du, Wenfeng Song, Jian Chen, Hao Chen, Zefeng Xuan, Long Zhao, Jun Chen, Cheng Jin, Mengqiao Zhou, Biguang Tuo, Yongchao Zhao, Shusen Zheng, Penghong Song
The intermediate conductance calcium-activated potassium channel (KCa3.1) plays an important role in maintaining intracellular calcium homeostasis and is involved in the tumorigenesis of many human cancers. However, it is unknown whether KCa3.1 plays a role in the genesis of hepatocellular carcinoma (HCC), one of the most common malignant tumors worldwide with a very poor prognosis. In this study, we found that the expression of KCa3.1 was significantly elevated in poorly differentiated HCC tissues compared with adjacent noncancerous tissues...
January 10, 2019: International Journal of Cancer. Journal International du Cancer
De Zeng, Yingsheng Xiao, Jianling Zhu, Chunyan Peng, Weiquan Liang, Haoyu Lin
Background: NPM1 is a multifunctional phosphoprotein that commutes between the cytoplasm and nucleus in cell cycle process, which appears to be actively involved in tumorigenesis. Herein, we sought to investigate the possible role and prognostic value of NPM1 in triple-negative breast cancer (TNBC). Methods: An array of public databases, including bc-GenExMiner v4.0, GOBO, GEPIA, UAL-CAN, ONCOMINE database and Kaplan-Meier plotter, were used to investigate the expression feature and potential function of NPM1 in TNBC...
2019: Cancer Management and Research
Yanan Lu, Shuting Song, Xiaoxue Jiang, Qiuyu Meng, Chen Wang, Xiaonan Li, Yuxin Yang, Xiaoru Xin, Qidi Zheng, Liyan Wang, Hu Pu, Xin Gui, Tianming Li, Dongdong Lu
miR675 is highly expressed in several human tumor tissues and positively regulates cell progression. Herein, we demonstrate that miR675 promotes malignant transformation of human mesenchymal stem cells. Mechanistically, we reveal that miR675 enhances the expression of the polyubiquitin-binding protein p62. Intriguingly, P62 competes with SETD2 to bind histone H3 and then significantly reduces SETD2-binding capacity to substrate histone H3, triggering drastically the reduction of three methylation on histone H3 36th lysine (H3K36me3)...
November 24, 2018: Molecular Therapy. Nucleic Acids
Lun Suo, Yu Xiao Zhou, Li Ling Jia, Hai Bo Wu, Jin Zheng, Qi Feng Lyu, Li Hua Sun, Han Sun, Yan Ping Kuang
There exist some patients who face recurrent total fertilization failure during assisted reproduction treatment, but the pathological mechanism underlying is elusive. Here, by using sc-RNA-seq method, the transcriptome profiles of ten abnormally fertilized zygotes were assessed, including five zygotes from one patient with recurrent Poly-PN zygotes, and five zygotes from a patient with pronuclear fusion failure. Four zygotes with three pronuclear (Tri-PN) were collected from four different patients as controls...
December 17, 2018: Scientific Reports
Wenhui Ma, Zhuoluo Xu, Yutian Wang, Wenyi Li, Zhigang Wei, Tao Chen, Tingyu Mou, Mingzhen Cheng, Jun Luo, Tingyue Luo, Yuehong Chen, Jiang Yu, Weijie Zhou, Guoxin Li
Rationale: This study is to validate the clinicopathologic significance and potential prognostic value of SLP2 in gastric cancer (GC), to investigate the biological function and regulation mechanism of SLP2, and to explore potential therapeutic strategies for GC. Methods: The expression of SLP2 in GC tissues from two cohorts was examined by IHC. The biological function and regulation mechanism of SLP2 and PHB was validated via loss-of-function or gain-of-function experiments. In vitro proliferation detection was used to evaluate the therapeutic effects of Sorafenib...
2018: Theranostics
Ling Bi, Chanlu Xie, Mu Yao, Su Su Thae Hnit, Soma Vignarajan, Yilun Wang, Qian Wang, Zhichao Xi, Hongxi Xu, Zhong Li, Paul de Souza, Andrew Tee, Matthew Wong, Tao Liu, Xiaodong Zhao, Jia Zhou, Ling Xu, Qihan Dong
Cancer cell repopulation through cell cycle re-entry by quiescent (G0 ) cell is thought to be an important mechanism behind treatment failure and cancer recurrence. Facilitates Chromatin Transcription (FACT) is involved in DNA repair, replication and transcription by eviction of histones or loosening their contact with DNA. While FACT expression is known to be high in a range of cancers, the biological significance of the aberrant increase is not clear. We found that in prostate and lung cancer cells FACT mRNA and protein levels were low at G0 compared to the proliferating state but replenished upon cell cycle re-entry...
December 13, 2018: International Journal of Cancer. Journal International du Cancer
Rui Zhang, Jing-Jing Hong, Qiaoyun Yang, Chin-Tong Ong, Bo-An Li, Yih-Cherng Liou
Poly(ADP-ribosyl)ation (PARylation) is a post-translational modification by which poly ADP-ribose (PAR) polymers are covalently added to proteins through a PAR polymerase (PARP). Here, using proteomic approach, we identify the transcriptional regulator, OVOL2, is a novel substrate of PARP1 and can be PARylated at residues Lysine 145, Lysine 176, and Lysine 212 within its C2H2 zinc finger domains. Overexpression of PARylated OVOL2 alters cell morphology and induces lagging chromosomes and aneuploidy. To define the underlying molecular mechanism by which OVOL2 induces abnormal cell cycle and centrosome amplification, we uncover that the OVOL2 elevates the protein levels of Cyclin E by enhancing its stability...
December 12, 2018: Oncogene
Yun-Cheol Chae, Ji-Young Kim, Jin Woo Park, Kee-Beom Kim, Hyein Oh, Kyung-Hwa Lee, Sang-Beom Seo
Posttranslational modifications of the Forkhead family transcription factor, FOXO1, have been known to have important regulatory implications in its diverse activities. Several types of modifications of FOXO1, including acetylation, phosphorylation, and ubiquitination, have been reported. However, lysine methylation of FOXO1 has not yet been identified. Here, we reported that FOXO1 is methylated by G9a at K273 residue in vitro and in vivo. Methylation of FOXO1 by G9a increased interaction between FOXO1 and a specific E3 ligase, SKP2, and decreased FOXO1 protein stability...
December 7, 2018: Nucleic Acids Research
Dan Wang, Xing Xu, Yue Wu, Yong Lin, Minhui Gao, Peili Hu, Dongjian Chen, Xu Lu, Zhuo Chen, Hui Wang, Chao Huang
This study was designed to examine the potency of SMIP004, an inhibitor of S-phase kinase-associated protein 2 (Skp2), to exert antidepressant-like properties in mouse models following acute or chronic administration to C57BL6/J mice. To this end, the tail suspension test (TST), forced swim test (FST), and sucrose preference test (SPT) were utilized and the antidepressant-like activity of SMIP004 at different concentrations or time points in mice with or without chronic unpredictable stress (CUS) treatment were evaluated...
November 28, 2018: European Journal of Pharmacology
Almudena Chaves-Pérez, Sebastian Thompson, Nabil Djouder
Almost 15 years ago, the URI prefoldin-like complex was discovered by Krek and colleagues in immunoprecipitation experiments conducted in mammalian cells with the aim of identifying new binding partners of the E3 ubiquitin-protein ligase S-phase kinase-associated protein 2 (SKP2) (Gstaiger et al. Science 302(5648):1208-1212, 2003). The URI prefoldin-like complex is a heterohexameric chaperone complex comprising two α and four β subunits (α2β4). The α subunits are URI and STAP1, while the β subunits are PFDN2, PFDN6, and PFDN4r, one of which is probably present in duplicate...
2018: Advances in Experimental Medicine and Biology
Yi-Chun Tsai, Po-Lin Kuo, Mei-Chuan Kuo, Wei-Wen Hung, Ling-Yu Wu, Wei-An Chang, Ping-Hsun Wu, Su-Chu Lee, Hung-Chun Chen, Ya-Ling Hsu
Diabetic nephropathy (DN) is the major cause of end stage renal disease. Proximal tubular epithelial cell (PTEC) injury occurs early in diabetic kidney, and it is correlated with consequent renal failure. Cellular senescence participates in the pathophysiology of DN, but its role remains unclear. We conducted a cross-disciplinary study, including human, in vivo, and in vitro studies, to explore the novel molecular mechanisms of PTEC senescence in DN. We found that HG induced cell senescence in PTECs, supported by enhanced β-galactosidase staining, p53 and p27 expression, and reduced cyclin E levels...
November 22, 2018: Journal of Clinical Medicine
Xiaochen Wang, Shizhen Zhang, Tao Zhang, Jinlan Shan
INTRODUCTION: F-box proteins are the substrate-recognizing subunits of SKP1-cullin1-F-box protein (SCF) E3 ligase complexes that play pivotal roles in multiple cellular processes, including cell proliferation, apoptosis, angiogenesis, invasion and metastasis. Dysregulation of F-box proteins may lead to an unbalanced proteolysis of numerous protein substrates, contributing to progression of human malignancies. However, the prognostic values of F-box members, especially at mRNA levels, in breast cancer are elusive...
October 19, 2018: Bioscience Reports
Abdul Q Khan, Kodappully S Siveen, Kirti S Prabhu, Shilpa Kuttikrishnan, Sabah Akhtar, Abdullah Shaar, Afsheen Raza, Fatima Mraiche, Said Dermime, Shahab Uddin
S-phase kinase-associated protein2 (Skp2), a proto-oncoprotein, plays an important role in development and progression of human malignancies. Skp2 is frequently overexpressed in many human malignancies. It targets cell cycle progression through ubiquitin mediated degradation of G1-checkpoint CDK inhibitors-p21 (CDKN1A) and p27 (CDKN1B). We investigated the role of Skp2 and its ubiquitin-proteasome pathway in head and neck squamous cell carcinoma (HNSCC) using a panel of cell lines with and without human papillomavirus (HPV+ , HPV- )...
2018: Frontiers in Oncology
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