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Lea Lough, Dan Sherman, Eric Ni, Lauren M Young, Bing Hao, Timothy Cardozo
Skp2 is a member of the F-box family of proteins that serve as substrate-specific adaptors in Skp1-CUL1-ROC1-F-box (SCF) E3 ubiquitin ligases. Skp2 (Fbxl1) directly binds to the tumor suppressor p27 in the context of the SCFSkp2 E3 ubiquitin ligase to ubiquitylate and target-phosphorylated p27 for proteasomal degradation. As p27 is a powerful suppressor of growth in a variety of cells, and as Skp2 is also overexpressed in many human cancers, Skp2 is considered an oncogene and an intriguing drug target. However, despite 20 years of investigation, a valid chemical inhibitor of Skp2-mediated degradation of p27 has not been identified...
July 1, 2018: MedChemComm
Hongshun Shi, Hui Li, Ronghua Yuan, Wen Guan, Xiaomei Zhang, Shaoyang Zhang, Wenliang Zhang, Fang Tong, Li Li, Zhihong Song, Changwei Wang, Shulan Yang, Haihe Wang
BACKGROUND: Poly C Binding Protein 1 (PCBP1) is an RNA-binding protein that binds and regulates translational activity of subsets of cellular mRNAs. Depletion of PCBP1 is implicated in various carcinomas, but the underlying mechanism in tumorigenesis remains elusive. METHODS: We performed a transcriptome-wide screen to identify novel bounding mRNA of PCBP1. The bind regions between PCBP1 with target mRNA were investigated by using point mutation and luciferase assay...
August 7, 2018: Journal of Experimental & Clinical Cancer Research: CR
Xing Wang, Chunyan Cheng, Kaijing Zhang, Zhen Tian, Jian Xu, Shuqiong Yang, Qunfeng Lou, Ji Li, Jin-Feng Chen
BACKGROUND: Meloidogyne incognita is a devastating nematode that causes significant losses in cucumber production worldwide. Although numerous studies have emphasized on the susceptible response of plants after nematode infection, the exact regulation mechanism of M. incognita-resistance in cucumber remains elusive. Verification of an introgression line, 'IL10-1', with M. incognita-resistance provides the opportunity to unravel the resistance mechanism of cucumber against M. incognita...
August 3, 2018: BMC Genomics
Mohammad Faujul Kabir, Johari Mohd Ali, Onn Haji Hashim
Background: We have previously reported anticancer activities of Melicope ptelefolia (MP) leaf extracts on four different cancer cell lines. However, the underlying mechanisms of actions have yet to be deciphered. In the present study, the anticancer activity of MP hexane extract (MP-HX) on colorectal (HCT116) and hepatocellular carcinoma (HepG2) cell lines was characterized through microarray gene expression profiling. Methods: HCT116 and HepG2 cells were treated with MP-HX for 24 hr...
2018: PeerJ
Sang-Min Jang, Ya Zhang, Koichi Utani, Haiqing Fu, Christophe E Redon, Anna B Marks, Owen K Smith, Catherine J Redmond, Adrian M Baris, Danielle A Tulchinsky, Mirit I Aladjem
Cell cycle progression in mammals is modulated by two ubiquitin ligase complexes, CRL4 and SCF, which facilitate degradation of chromatin substrates involved in the regulation of DNA replication. One member of the CRL4 complex, the WD-40 containing protein RepID (DCAF14/PHIP), selectively binds and activates a group of replication origins. Here we show that RepID recruits the CRL4 complex to chromatin prior to DNA synthesis, thus playing a crucial architectural role in the proper licensing of chromosomes for replication...
July 17, 2018: Nature Communications
Sara E Meyer, David E Muench, Andrew M Rogers, Tess J Newkold, Emily Orr, Eric O'Brien, John P Perentesis, John G Doench, Ashish Lal, Patrick J Morris, Craig J Thomas, Judy Lieberman, Edwina McGlinn, Bruce J Aronow, Nathan Salomonis, H Leighton Grimes
We have shown that antagomiR inhibition of miRNA miR-21 and miR-196b activity is sufficient to ablate MLL-AF9 leukemia stem cells (LSC) in vivo. Here, we used an shRNA screening approach to mimic miRNA activity on experimentally verified miR-196b targets to identify functionally important and therapeutically relevant pathways downstream of oncogenic miRNA in MLL-r AML. We found Cdkn1b (p27Kip1 ) is a direct miR-196b target whose repression enhanced an embryonic stem cell-like signature associated with decreased leukemia latency and increased numbers of leukemia stem cells in vivo...
August 6, 2018: Journal of Experimental Medicine
Xiaoshuang Wei, Xu Li, Wei Yan, Xinghua Zhang, Yu Sun, Feng Zhang
BACKGROUND/AIMS: SKP2 overexpression has been associated with poor prognosis in numerous cancers. The mechanisms of autophagy in the tumor pathogenesis have been a research focus recently. How the SKP2 involved in autophagy expresses oncogenic characteristics, especially in HCC, are largely unclear. METHODS: The expression of SKP2 was detected by qPCR, Western blot, Immunohistochemical (IHC) and Immunofluorescence (IF) techniques. SKP2 was knocked down or overexpressed by lentivirus transfection in HCC cells...
2018: Cellular Physiology and Biochemistry
Yan Zhang, Xinyi Mu, Rufei Gao, Yanqing Geng, Xueqing Liu, Xuemei Chen, Yuheng Wang, Yubin Ding, Yingxiong Wang, Junlin He
The female reproductive lifespan is largely determined by the size of the primordial follicle pool, which is established early in life. We previously reported that Di (2-ethylhexyl) phthalate (DEHP), an environmental endocrine disruptor and a widely-spreading plasticizer, impairs primordial folliculogenesis. In the present study, we found DEHP significantly altered the number and sex ratio of the offspring of neonatal-exposed mice. Furthermore, by a neonatal exposure model and an ovary culture model, it showed that DEHP activated autophagy in the ovary, with increased autophagy-related gene expression and recognizable autophagosomes, while inhibition of autophagy by 3-MA attenuated the adverse impact of DEHP on primordial folliculogenesis...
September 15, 2018: Journal of Hazardous Materials
Ma'anit Shapira, Eli Kakiashvili, Tzur Rosenberg, Dan D Hershko
After the publication of this work [1], an error was noticed in Fig. 2b, Fig. 3a and Fig. 5b. The Skp1 loading control was accidentally duplicated. We apologize for this error, which did not affect any of the interpretations or conclusions of the article.
July 9, 2018: Breast Cancer Research: BCR
Rachel Brough, Aditi Gulati, Syed Haider, Rahul Kumar, James Campbell, Erik Knudsen, Stephen J Pettitt, Colm J Ryan, Christopher J Lord
Although defects in the RB1 tumour suppressor are one of the more common driver alterations found in triple-negative breast cancer (TNBC), therapeutic approaches that exploit this have not been identified. By integrating molecular profiling data with data from multiple genetic perturbation screens, we identified candidate synthetic lethal (SL) interactions associated with RB1 defects in TNBC. We refined this analysis by identifying the highly penetrant effects, reasoning that these would be more robust in the face of molecular heterogeneity and would represent more promising therapeutic targets...
June 18, 2018: Oncogene
Shuyuan Liu, Jinhua Wan, Yunyuan Kong, Yonglu Zhang, Lagen Wan, Zhanglin Zhang
The cullin-RING ligase (CRL)-NEDD8 pathway maintains essential cellular processes, including cell cycle progression, apoptosis, autophagy, DNA repair, antigen processing and signal transduction. Growing evidence demonstrates that the alteration of the CRL-NEDD8 pathway in some cancers constitutes an attractive target for therapeutic intervention, but the roles of CRL-NEDD8 pathway in acute promyelocytic leukemia (APL) is still unclear. In the present study, we found that ATRA could decrease the expression of NEDD8-activating enzyme E1 (NAE1) and inhibit the neddylation of cullin1 and cullin3 in the APL cell line NB4...
2018: International Journal of Medical Sciences
Uros Midic, Kailey A Vincent, Kai Wang, Alyson Lokken, Ashley L Severance, Amy Ralston, Jason G Knott, Keith E Latham
Structural maintenance of chromosome flexible domain containing 1 (Smchd1) is a chromatin regulatory gene for which mutations are associated with facioscapulohumeral muscular dystrophy and arhinia. The contribution of oocyte- and zygote-expressed SMCHD1 to early development was examined in mice (Mus musculus) using an siRNA knockdown approach. Smchd1 knockdown compromised long-term embryo viability, with reduced embryo nuclear volumes at the morula stage, reduced blastocyst cell number, formation and hatching, and reduced viability to term...
June 13, 2018: Molecular Reproduction and Development
Yuwen Chen, Wenhua Li, Zhongqiu Zeng, Yaxiong Tang
With limited success achieved in bladder cancer patient management, novel agents are in urgent need for the purpose of therapy and prevention. As a sesquiterpenoid dimmer isolated from Gochnatia pomculat, (-)-gochnatiolide B has been bio-mimetically synthesized in multiple steps with a poor yield, which heavily limited the further research and clinical application. Herein, (-)-gochnatiolide B was synthesized beginning with dehydrocostuslactone in four steps with a total yield of 26%. MTT assays showed that (-)-gochnatiolide B inhibited the growth of vast majority of human cancer cells especially bladder cancer cells...
June 11, 2018: Scientific Reports
Fan Yao, Zhicheng Zhou, Jongchan Kim, Qinglei Hang, Zhenna Xiao, Baochau N Ton, Liang Chang, Na Liu, Liyong Zeng, Wenqi Wang, Yumeng Wang, Peijing Zhang, Xiaoyu Hu, Xiaohua Su, Han Liang, Yutong Sun, Li Ma
Dysregulation of YAP localization and activity is associated with pathological conditions such as cancer. Although activation of the Hippo phosphorylation cascade is known to cause cytoplasmic retention and inactivation of YAP, emerging evidence suggests that YAP can be regulated in a Hippo-independent manner. Here, we report that YAP is subject to non-proteolytic, K63-linked polyubiquitination by the SCFSKP2 E3 ligase complex (SKP2), which is reversed by the deubiquitinase OTUD1. The non-proteolytic ubiquitination of YAP enhances its interaction with its nuclear binding partner TEAD, thereby inducing YAP's nuclear localization, transcriptional activity, and growth-promoting function...
June 11, 2018: Nature Communications
Lili He, Kebo Gu
Mitophagy is important for cancer development. Notably, the role of Parkin‑mediated mitophagy in colorectal cancer (CRC) mortality has not been fully determined. Therefore, the present study aimed to investigate the effect of Parkin‑mediated mitophagy on CRC apoptosis. In addition, the present study investigated the therapeutic effects of Tanshinone IIA (Tan IIA) on the regulation of CRC cell death via mitophagy. Cellular apoptosis was measured following Tan IIA treatment. In addition, mitophagy activity was evaluated by immunofluorescence and western blotting...
August 2018: Molecular Medicine Reports
Yawen Tan, Guanglin Zhou, Xianming Wang, Weicai Chen, Haidong Gao
Recent studies have suggested that ubiquitin-specific peptidase (USP)18 may act as an oncogene in various types of cancer. Although the role of USP18 in breast cancer cell lines has been elucidated, the underlying mechanisms and clinical role of USP18 in breast cancer are currently not well understood. The bioinformatics analysis and experimental results of the present study demonstrated that aberrant promoter methylation led to increased expression of USP18 in breast cancer. In addition, correlation analysis suggested that a negative correlation between methylation and USP18 mRNA expression was observed in The Cancer Genome Atlas database...
July 2018: International Journal of Oncology
Yu-Shih Lin, Yin-Yin Lin, Yao-Hsu Yang, Chun-Liang Lin, Feng-Che Kuan, Cheng-Nan Lu, Geng-He Chang, Ming-Shao Tsai, Cheng-Ming Hsu, Reming-Albert Yeh, Pei-Rung Yang, I-Yun Lee, Li-Hsin Shu, Yu-Ching Cheng, Hung-Te Liu, Kuan-Der Lee, De-Ching Chang, Ching-Yuan Wu
BACKGROUND: Breast cancer is the most common cancer in women and affects 1.38 million women worldwide per year. Antiestrogens such as tamoxifen, a selective estrogen receptor (ER) modulator, are widely used in clinics to treat ER-positive breast tumors. However, remissions of breast cancer are often followed by resistance to tamoxifen and disease relapse. Despite the increasing understanding of the resistance mechanisms, effective regimens for treating tamoxifen-resistant breast cancer are limited...
May 9, 2018: BMC Complementary and Alternative Medicine
Lu Ding, Chengwei Wang, Yong Cui, Xiaoping Han, Yang Zhou, Jingping Bai, Rong Li
Osteosarcoma (OS), a common worldwide primary aggressive bone malignancy, arises from primitive transformed cells of mesenchymal origin and usually attacks adolescents and young adults. Methotrexate (MTX) is the anti-folate drug used as a pivotal chemotherapeutic agent in the treatment of OS. However, patients with OS often develop drug resistance, leading to poor treatment outcomes. In the present study, in order to explore the underlying mechanisms responsible for MTX resistance, we established MTX‑resistant OS cells using the U2OS and MG63 cell lines and examined whether MTX‑resistant OS cells underwent epithelial-mesenchymal transition (EMT) by Transwell assay, wound healing assay, MTT assay, RT-PCR and western blot analysis...
June 2018: International Journal of Oncology
Karnika Singh, Qin Dong, Prakash S TimiriShanmugam, Sweaty Koul, Hari K Koul
Current therapies in Pancreatic Cancer (PaCa) are ineffective due to deregulated cell cycle driven by landscape mutations. In this study, we show for the first time that tetrandrine (TET) inhibits proliferation of the PaCa cells and inhibits PaCa tumor growth. TET inhibits cell cycle transition at G1/S boundary. TET increased levels of p21Cip1/Waf1 and p27Kip1 , had no effect on the levels of CDK4/6 proteins and decreased the levels of cyclin D1 and pRb proteins. TET resulted in changes in mRNA levels of cyclin D1 and p21Cip1/Waf1 but had no effect on the mRNA of p27Kip1 ...
July 1, 2018: Cancer Letters
Chu-Fang Chou, Yu-Hua Hsieh, Clinton J Grubbs, Venkatram R Atigadda, James A Mobley, Reinhard Dummer, Donald D Muccio, Isao Eto, Craig A Elmets, W Timothy Garvey, Pi-Ling Chang
BACKGROUND: Bexarotene (Targretin® ) is currently the only FDA approved retinoid X receptor (RXR) -selective agonist for the treatment of cutaneous T-cell lymphomas (CTCLs). The main side effects of bexarotene are hypothyroidism and elevation of serum triglycerides (TGs). The novel RXR ligand, 9-cis UAB30 (UAB30) does not elevate serum TGs or induce hypothyroidism in normal subjects. OBJECTIVES: To assess preclinical efficacy and mechanism of action of UAB30 in the treatment of CTCLs and compare its action with bexarotene...
June 2018: Journal of Dermatological Science
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