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Role of AP-1 Antagonism in Growth Inhibition of Cervical Cancer Cell Lines by Retinoids

Shennan Lu, Doris M. Benbrook
2006 American Journal of Pharmacology and Toxicology  
Retinoid compounds induce multiple molecular effects that need to be taken into consideration in the development of theses agents as pharmaceuticals for cancer chemoprevention. Inhibition of cancer cell growth by retinoids is thought to occur through at least two mechanisms of transcriptional regulation resulting from direct binding of retinoids to nuclear retinoid receptors (RARs and RXR's). First, the nuclear receptors induce or repress expression of specific genes by direct binding to
more » ... c acid response elements (RAREs) in gene promoters. Second, the nuclear receptors antagonize transactivation of activator protein-1 (AP-1) promoter elements by the AP-1 transcription factors. The objective of this study was to determine the contributions of RARE transactivation and AP-1 antagonism to the mechanism of growth inhibition in cervical cancer cell lines by: the 9-cis isomer of retinoic acid (9-cis-RA), which binds both RARs and RXRs; and a series of synthetic retinoids, called heteraoarotinoids, that possess various receptor specificities and reduced toxicity. The effects of these compounds on reporter gene expression and proliferation were measured in CC-1 and SiHa cell lines stably transfected with RARE or AP-1 reporter plasmids or a retrovirus harboring an inducibile AP-1 protein that is a dominant negative mutant of c-Jun (TAM67). In the CC-1 cell line, which exhibited high AP-1 activity, retinoid growth inhibition significantly correlated with both RARE transactivation and AP-1 repression, was antagonized by superinduction of AP-1 with TPA (12-O-tetradecanoylphorbol-13-acetate) and was enhanced by TAM67. In the SiHa cell line, which exhibited low AP-1 activity, RARE transactivation also significantly correlated with growth inhibition, but AP-1 induction, in contrast to AP-1 repression, correlated with growth inhibition. Furthermore, TPA superinduction of AP-1 did not attenuate retinoid growth inhibition activity in SiHa. In conclusion, repression of AP-1 with retinoids may only be effective against a subset of tumors with high AP-1 activity.
doi:10.3844/ajptsp.2006.40.47 fatcat:ugyyu3a6yjfjxog5kgw6pjraw4

Biological Assay for Activity and Molecular Mechanism of Retinoids in Cervical Tumor Cells

Doris M. Benbrook, Shennan Lu, Cole Flanagan, Jane Shen-Gunther, Lee H. Angros, Stan A. Lightfoot
1997 Gynecologic Oncology  
but in the United States, Canada, and Western Europe early The composition and response of the retinoid signaling pathway detection of precursor lesions with Papincolaou (PAP) smear in a human cell line (CC-1), representative of a low grade cervical screening programs has greatly decreased the mortality of carcinoma, were evaluated. Reverse-transcriptase polymerase this disease [8]. The human papillomavirus (HPV) has been chain reaction (RT-PCR) analysis demonstrated expression of cyidentified
more » ... n the vast majority of cervical tumors and is betoplasmic retinol binding protein, CRBPI, cytoplasmic retinoic lieved to be an etiologic agent in the development of this acid binding protein, CRABPII, and nuclear retinoic acid recepdisease. HPV types 16, 18, 31, and 33 are most frequently tors, RARa, RARg, RXRa, and RXRb, but not CRABPI or found in advanced cancer and are considered to be of the RARb. This pattern is similar to that of the ectocervix. Activation high risk type [9]. of endogenous nuclear receptors was evaluated in a reporter sub-Transfection of type 16 or 18 HPV DNA into normal line of CC-1, called CC-B, containing a reporter gene controlled by epithelial cells induces immortalization (unlimited growth a retinoic acid responsive element (RARE) and thymidine kinase promoter. Retinoid treatment of CC-B resulted in dose-dependent potential) and increased epidermal growth factor receptor increases in reporter gene expression. Retinoids inhibited growth (EGF-R) expression [10-12]. In normal epithelium, EGFat concentrations greater than 100 nM. 9-cis retinoic acid (1 nM) R is expressed in the proliferating basal cells and is decreased significantly stimulated growth. Immunohistochemical analysis of or not expressed with increasing differentiation of cells to-CC-B organotypic cultures demonstrated a high level of epidermal ward the mucosal surface [13, 14]. An increase in the number growth factor receptor (EGF-R) expression that was decreased by of cells expressing EGF-R is observed in squamous intraepiretinoids. The degree of RARE transactivation induced by retithelial lesions (SIL) of the cervix [13, 14]. The higher grade noids significantly correlated with the degree of inhibition of of SILs exhibit a greater percentage of proliferating cells growth (R Å 0 0.96) and EGF-R expression (R Å 0 0.92). The doseand a corresponding increase in the numbers of EGF-Rdependent and retinoid-specific responses of CC-1 at the molecular expressing cells. This results in a positive correlation beand biological levels demonstrate the utility of this reporter cell line for evaluation of retinoid activities. ᭧ 1997 Academic Press tween grade of tumor and EGF-R expression. In invasive squamous cervical carcinoma, overexpression of EGF-R has been associated with biological aggressiveness of the tumor
doi:10.1006/gyno.1997.4736 pmid:9234931 fatcat:25pm24azizfvde4tmofmfzpnie

CDD: NCBI's conserved domain database

Aron Marchler-Bauer, Myra K. Derbyshire, Noreen R. Gonzales, Shennan Lu, Farideh Chitsaz, Lewis Y. Geer, Renata C. Geer, Jane He, Marc Gwadz, David I. Hurwitz, Christopher J. Lanczycki, Fu Lu (+8 others)
2014 Nucleic Acids Research  
NCBI's CDD, the Conserved Domain Database, enters its 15 th year as a public resource for the annotation of proteins with the location of conserved domain footprints. Going forward, we strive to improve the coverage and consistency of domain annotation provided by CDD. We maintain a live search system as well as an archive of pre-computed domain annotation for sequences tracked in NCBI's Entrez protein database, which can be retrieved for single sequences or in bulk. We also maintain import
more » ... edures so that CDD contains domain models and domain definitions provided by several collections available in the public domain, as well as those produced by an in-house curation effort. The curation effort aims at increasing coverage and providing finergrained classifications of common protein domains, for which a wealth of functional and structural data has become available. CDD curation generates alignment models of representative sequence fragments, which are in agreement with domain boundaries as observed in protein 3D structure, and which model the structurally conserved cores of domain families as well as annotate conserved features. CDD can be accessed at cdd/cdd.shtml.
doi:10.1093/nar/gku1221 pmid:25414356 pmcid:PMC4383992 fatcat:fmwggydorjhetcwv6griivaci4

CDD: conserved domains and protein three-dimensional structure

Aron Marchler-Bauer, Chanjuan Zheng, Farideh Chitsaz, Myra K. Derbyshire, Lewis Y. Geer, Renata C. Geer, Noreen R. Gonzales, Marc Gwadz, David I. Hurwitz, Christopher J. Lanczycki, Fu Lu, Shennan Lu (+6 others)
2012 Nucleic Acids Research  
CDD, the Conserved Domain Database, is part of NCBI's Entrez query and retrieval system and is also accessible via Structure/cdd/cdd.shtml. CDD provides annotation of protein sequences with the location of conserved domain footprints and functional sites inferred from these footprints. Pre-computed annotation is available via Entrez, and interactive search services accept single protein or nucleotide queries, as well as batch submissions of protein query sequences,
more » ... tilizing RPS-BLAST to rapidly identify putative matches. CDD incorporates several protein domain and full-length protein model collections, and maintains an active curation effort that aims at providing fine grained classifications for major and wellcharacterized protein domain families, as supported by available protein three-dimensional (3D) structure and the published literature. To this date, the majority of protein 3D structures are represented by models tracked by CDD, and CDD curators are characterizing novel families that emerge from protein structure determination efforts.
doi:10.1093/nar/gks1243 pmid:23197659 pmcid:PMC3531192 fatcat:kyfhbmseffcrjpuj7ie33t7trq

Class I histone deacetylases are major histone decrotonylases: evidence for critical and broad function of histone crotonylation in transcription

Wei Wei, Xiaoguang Liu, Jiwei Chen, Shennan Gao, Lu Lu, Huifang Zhang, Guangjin Ding, Zhiqiang Wang, Zhongzhou Chen, Tieliu Shi, Jiwen Li, Jianjun Yu (+1 others)
2017 Cell Research  
Lu Lu, Huifang Zhang and Guangjin Ding participated in screening for HDCRs. Shennan Gao and Zhiqiang Wang performed ES cells-related experiments. Zhongzhou Chen designed HDAC1 mutant.  ... 
doi:10.1038/cr.2017.68 pmid:28497810 pmcid:PMC5518989 fatcat:t5ubjlqnzrbmbmr45uvqb3rc6i

Annexin A1 promotes the progression of bladder cancer via regulating EGFR signaling pathway

Piao Li, Lingling Li, Zhou Li, Shennan Wang, Ruichao Li, Weiheng Zhao, Yanqi Feng, Shanshan Huang, Lu Li, Hong Qiu, Shu Xia
2022 Cancer Cell International  
Background Bladder cancer (BLCA) is one of the most common malignancies worldwide. One of the main reasons for the unsatisfactory management of BLCA is the complex molecular biological mechanism. Annexin A1 (ANXA1), a Ca2+-regulated phospholipid-binding protein, has been demonstrated to be implicated in the progression and prognosis of many cancers. However, the expression pattern, biological function and mechanism of ANXA1 in BLCA remain unclear. Methods The clinical relevance of ANXA1 in BLCA
more » ... was investigated by bioinformatics analysis based on TCGA and GEO datasets. Immunohistochemical (IHC) analysis was performed to detect the expression of ANXA1 in BLCA tissues, and the relationships between ANXA1 and clinical parameters were analyzed. In vitro and in vivo experiments were conducted to study the biological functions of ANXA1 in BLCA. Finally, the potential mechanism of ANXA1 in BLCA was explored by bioinformatics analysis and verified by in vitro and in vivo experiments. Results Bioinformatics and IHC analyses indicated that a high expression level of ANXA1 was strongly associated with the progression and poor prognosis of patients with BLCA. Functional studies demonstrated that ANXA1 silencing inhibited the proliferation, migration, invasion and epithelial–mesenchymal transition (EMT) of BLCA cells in vitro, and suppressed the growth of xenografted bladder tumors in vivo. Mechanistically, loss of ANXA1 decreased the expression and phosphorylation level of EGFR and the activation of downstream signaling pathways. In addition, knockdown of ANXA1 accelerated ubiquitination and degradation of P-EGFR to downregulate the activation of EGFR signaling. Conclusions These findings indicate that ANXA1 is a reliable clinical predictor for the prognosis of BLCA and promotes proliferation and migration by activating EGFR signaling in BLCA. Therefore, ANXA1 may be a promising biomarker for the prognosis of patients with BLCA, thus shedding light on precise and personalized therapy for BLCA in the future.
doi:10.1186/s12935-021-02427-4 pmid:34991599 pmcid:PMC8740017 fatcat:g7fihji4xfh2zkjqd2bqxfi5hq

CDD/SPARCLE: functional classification of proteins via subfamily domain architectures

Aron Marchler-Bauer, Yu Bo, Lianyi Han, Jane He, Christopher J. Lanczycki, Shennan Lu, Farideh Chitsaz, Myra K. Derbyshire, Renata C. Geer, Noreen R. Gonzales, Marc Gwadz, David I. Hurwitz (+10 others)
2016 Nucleic Acids Research  
NCBI's Conserved Domain Database (CDD) aims at annotating biomolecular sequences with the location of evolutionarily conserved protein domain footprints, and functional sites inferred from such footprints. An archive of pre-computed domain annotation is maintained for proteins tracked by NCBI's Entrez database, and live search services are offered as well. CDD curation staff supplements a comprehensive collection of protein domain and protein family models, which have been imported from
more » ... providers, with representations of selected domain families that are curated in-house and organized into hierarchical classifications of functionally distinct families and sub-families. CDD also supports comparative analyses of protein families via conserved domain architectures, and a recent curation effort focuses on providing functional characterizations of distinct subfamily architectures using SPARCLE: Subfamily Protein Architecture Labeling Engine. CDD can be accessed at https://www.ncbi.
doi:10.1093/nar/gkw1129 pmid:27899674 pmcid:PMC5210587 fatcat:uwnork4w2bfhrovmauui7o5ejm

iCn3D, a Web-based 3D Viewer for Sharing 1D/2D/3D Representations of Biomolecular Structures [article]

Jiyao Wang, Philippe Youkharibache, Dachuan Zhang, Christopher J Lanczycki, Renata C Geer, Tom Madej, Lon Phan, Minghong Ward, Shennan Lu, Gabriele H Marchler, Yanli Wang, Stephen H Bryant (+2 others)
2018 bioRxiv   pre-print
iCn3D (I-see-in-3D) is a web-based 3D molecular structure viewer focusing on the interactive structural analysis. It can simultaneously show 3D structure, 2D molecular contacts, and 1D protein and nucleotide sequences through an integrated sequence/annotation browser. Pre-defined and arbitrary molecular features can be selected in any of the 1D/2D/3D windows as sets of residues and these selections are synchronized dynamically in all displays. Biological annotations such as protein domains,
more » ... le nucleotide variations, etc. can be shown as tracks in the 1D sequence/annotation browser. These customized displays can be shared with colleagues or publishers via a simple URL. iCn3D can display structure-structure alignment obtained from NCBI's VAST+ service. It can also display the alignment of a sequence with a structure as identified by BLAST, and thus relate 3D structure to a large fraction of all known proteins. iCn3D can also display electron density maps or electron microscopy (EM) density maps, and export files for 3D printing. The following example URL exemplifies some of the 1D/2D/3D representations:
doi:10.1101/501692 fatcat:fdgmpjo5tffptmtd4wlyuf335u

iCn3D: from Web-based 3D Viewer to Structure Analysis Tool in Batch Mode [article]

Jiyao Wang, Philippe Youkharibache, Aron Marchler-Bauer, Christopher Lanczycki, Dachuan Zhang, Shennan Lu, Thomas Madej, Gabriele H. Marchler, Tiejun Cheng, Li Chuin Chong, Sarah Zhao, Kevin Yang (+11 others)
2021 bioRxiv   pre-print
iCn3D was originally released as a web-based 3D viewer, which allows users to create a custom view in a life-long, shortened URL to share with colleagues. Recently, iCn3D was converted to use JavaScript classes and could be used as a library to write Node.js scripts. Any interactive features in iCn3D can be converted to Node.js scripts to run in batch mode for a large data set. Currently the following Node.js script examples are available at
more » ... igand-protein interaction, protein-protein interaction, change of interactions due to residue mutations, DelPhi electrostatic potential, and solvent accessible surface area. iCn3D PNG images can also be exported in batch mode using a Python script. Other recent features of iCn3D include the alignment of multiple chains from different structures, realignment, dynamic symmetry calculation for any subsets, 2D cartoons at different levels, and interactive contact maps. iCn3D can also be used in Jupyter Notebook as described at
doi:10.1101/2021.09.10.459868 fatcat:wl526d6du5dobafdlioswq3ow4

iCn3D: From Web-Based 3D Viewer to Structural Analysis Tool in Batch Mode

Jiyao Wang, Philippe Youkharibache, Aron Marchler-Bauer, Christopher Lanczycki, Dachuan Zhang, Shennan Lu, Thomas Madej, Gabriele H. Marchler, Tiejun Cheng, Li Chuin Chong, Sarah Zhao, Kevin Yang (+11 others)
2022 Frontiers in Molecular Biosciences  
iCn3D was initially developed as a web-based 3D molecular viewer. It then evolved from visualization into a full-featured interactive structural analysis software. It became a collaborative research instrument through the sharing of permanent, shortened URLs that encapsulate not only annotated visual molecular scenes, but also all underlying data and analysis scripts in a FAIR manner. More recently, with the growth of structural databases, the need to analyze large structural datasets
more » ... ally led us to use Python scripts and convert the code to be used in Node. js scripts. We showed a few examples of Python scripts at to export secondary structures or PNG images from iCn3D. Users just need to replace the URL in the Python scripts to export other annotations from iCn3D. Furthermore, any interactive iCn3D feature can be converted into a Node. js script to be run in batch mode, enabling an interactive analysis performed on one or a handful of protein complexes to be scaled up to analysis features of large ensembles of structures. Currently available Node. js analysis scripts examples are available at This development will enable ensemble analyses on growing structural databases such as AlphaFold or RoseTTAFold on one hand and Electron Microscopy on the other. In this paper, we also review new features such as DelPhi electrostatic potential, 3D view of mutations, alignment of multiple chains, assembly of multiple structures by realignment, dynamic symmetry calculation, 2D cartoons at different levels, interactive contact maps, and use of iCn3D in Jupyter Notebook as described at
doi:10.3389/fmolb.2022.831740 pmid:35252351 pmcid:PMC8892267 fatcat:tquvgkw25rg2xhcmsgjyqyqtzi

InterPro in 2017—beyond protein family and domain annotations

Robert D. Finn, Teresa K. Attwood, Patricia C. Babbitt, Alex Bateman, Peer Bork, Alan J. Bridge, Hsin-Yu Chang, Zsuzsanna Dosztányi, Sara El-Gebali, Matthew Fraser, Julian Gough, David Haft (+35 others)
2016 Nucleic Acids Research  
Please refer to any applicable terms of use of the publisher.
doi:10.1093/nar/gkw1107 pmid:27899635 pmcid:PMC5210578 fatcat:wa7z5pgpuffnrh5bf5ycimw7kq

Page 389 of Journal of the American College of Surgeons Vol. 40, Issue 3 [page]

1925 Journal of the American College of Surgeons  
Steindl reported a pure culture of an anaerobic bacil- lus in his case. Finney found no bacteria.  ...  Shennan and Wilkie found no organisms microscopically in the cysts or within their walls, in their case.  ... 

Page 497 of None Vol. 18, Issue 123 [page]

1805 None  
The Population £2, — | COUNTY OF ANGLESEA, f - eS et shennan !, | \} | \riTc ro ' ! ‘ Ea NOUSES. PERSONS. occupations. || x é j i?  ...  ; ' HUNDRED OF | } | | | SE 0. wih o-haierdwes au O42 | 1,159 2.490 | » 669 |) 4,14 | 997 || 5,339 : Crickhow el- li CH nc oe ai a ta 1,008 108% | "ean V0 95 LU } 699 YOY D016 } C | yr, >> (3 " { 4?  ... 

Page 236 of None Vol. 55, Issue 6 [page]

2004 None  
Lu R. Lucas J. MacDonald K. Machaca D. MacLennan R. MacLeod D. Madtes G. Makhlout L. Mangravite J. Marchant W. Marshall S. Martin D. Martyn E. Masliah L. Matherly F. Maxfield J. May A. McArdle J.  ...  Shennan X. Shi O. Shirthai A. Shuldiner S. Signoretti C. Silva S. Simon P. Smith Q. Smith M. Soleimani K. Solomon J. Solway D. Sorescu S. Sorota J. Sowers K. Spitzer M. Spurlock W. Stamer M. Stern J.  ... 
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