DOCSLIB.ORG

Impact of RUNX2 on Drug-Resistant Human Pancreatic Cancer Cells with P53 Mutations

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Impact of RUNX2 on Drug-Resistant Human Pancreatic Cancer Cells with P53 Mutations Ozaki et al. BMC Cancer (2018) 18:309 https://doi.org/10.1186/s12885-018-4217-9 REVIEWARTICLE Open Access Impact of RUNX2 on drug-resistant human pancreatic cancer cells with p53 mutations Toshinori Ozaki1*†, Meng Yu2†, Danjing Yin3, Dan Sun4, Yuyan Zhu4, Youquan Bu5 and Meixiang Sang3 Abstract Background: Despite the remarkable advances in the early diagnosis and treatment, overall 5-year survival rate of patients with pancreatic cancer is less than 10%. Gemcitabine (GEM), a cytidine nucleoside analogue and ribonucleotide reductase inhibitor, is a primary option for patients with advanced pancreatic cancer; however, its clinical efficacy is extremely limited. This unfavorable clinical outcome of pancreatic cancer patients is at least in part attributable to their poor response to anti-cancer drugs such as GEM. Thus, it is urgent to understand the precise molecular basis behind the drug-resistant property of pancreatic cancer and also to develop a novel strategy to overcome this deadly disease. Review: Accumulating evidence strongly suggests that p53 mutations contribute to the acquisition and/or maintenance of drug-resistant property of pancreatic cancer. Indeed, certain p53 mutants render pancreatic cancer cells much more resistant to GEM, implying that p53 mutation is one of the critical determinants of GEM sensitivity. Intriguingly, runt-related transcription factor 2 (RUNX2) is expressed at higher level in numerous human cancers such as pancreatic cancer andosteosarcoma,indicatingthat,inadditiontoits pro-osteogenic role, RUNX2 has a pro-oncogenic potential. Moreover, a growing body of evidence implies that a variety of miRNAs suppress malignant phenotypes of pancreatic cancer cells including drug resistance through the down-regulation of RUNX2. Recently, we have found for the first time that forced depletion of RUNX2 significantly increases GEM sensitivity of p53-null as well as p53-mutated pancreatic cancer cells through the stimulation of p53 family TAp63/TAp73-dependent cell death pathway. Conclusions: Together, it is likely that RUNX2 is one of the promising molecular targets for the treatment of the patients with pancreatic cancer regardless of their p53 status. In this review article, we will discuss how to overcome the serious drug-resistant phenotype of pancreatic cancer. Keywords: Gemcitabine, Mutant p53, p53 family, RUNX2 Background the treatment of patients with advanced pancreatic can- Pancreatic cancer which is highly metastatic to lymph cer [3]. Unfortunately, its clinical efficacy is extremely nodes, liver and the other distal sites, is one of the most limited and the extensive efforts to develop the combin- lethal malignancies among human cancers with 5-year ation regimes with GEM have resulted in only a minor survival rate less than 10%, and its incidence is gradually improvement over the conventional therapies [4]. There- increasing worldwide [1]. Although 20% of patients re- fore, it is urgent to develop novel treatment options ceive surgical resection at diagnosis, the remaining 80% against pancreatic cancer, and also to understand the of patients are identified as unresectable due to their late precise molecular mechanisms how pancreatic cancer diagnosis [2]. Gemcitabine (GEM), a deoxycytidine cells could acquire and maintain GEM-resistant analogue, has become a standard chemotherapeutic for phenotype. As mentioned above, GEM resistance is a critical * Correspondence: [email protected] issue to be adequately addressed for the better treat- †Equal contributors ment of pancreatic cancer patients. Accumulating evi- 1 Laboratory of DNA Damage Signaling, Chiba Cancer Center Research dence strongly suggests that the alterations within Institute, Chiba 260-8717, Japan KRAS p53 CDKN2A SMAD4 Full list of author information is available at the end of the article , , and are frequently © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Ozaki et al. BMC Cancer (2018) 18:309 Page 2 of 15 detected in pancreatic cancer tissues, and contribute Main text to the genesis and/or maintenance of their advanced Pancreatic cancer phenotypes including GEM resistance [5]. Among Pancreatic cancer is ranked as the fourth leading cause these genetic aberrations, p53 mutations (around of cancer-related death in the world (both in industrial 75%) appear in the later stages of pancreatic cancer countries as well as nonindustrial ones), and is known to genesis and development [6, 7]. Since p53, which exhibit the worst prognosis among cancers (5-year sur- monitors and ensures the genomic integrity, is an es- vival rate is less than 10%) [24, 25]. Its mortality rate is sential molecular barrier against carcinogenesis [8, 9], nearly equal to its incidence. Up to 80% of pancreatic it is possible that loss of function mutation of p53 cancer deaths take place within the first year of diagno- leads to the accumulation of genetic damage within sis. Although surgical resection is the only potentially pancreatic cancer cells, and thus they might acquire curative approach against pancreatic cancer, greater than GEM-resistant property as well as metastatic 80% of cases are judged as unresectable at the time of potential. diagnosis due to its locally advanced property and/or RUNX2 (also called Osf2/Cbfa1, AML-3 or Peb- metastasis. A highly invasive and metastatic nature of p2αA), a member of RUNX (runt-related transcription the advanced pancreatic cancer is often responsible for factor) family, has been shown to be one of the major its extremely poor clinical outcome. Therefore, it is ur- determinants of osteoblast differentiation and bone gently required to identify the reliable diagnostic and/or formation [10]. As expected, RUNX2 transactivates prognostic markers. These biomarkers could be helpful number of pro-osteogenic target genes such as colla- to the accurate detection of pancreatic cancer in the gen type I, bone alkaline phosphatase, osteopontin early stage, and the prediction of its biological behavior. and osteocalcin [11]. In addition to its pro-osteogenic Because of the low chance of successful surgery, role,agrowingbodyofevidencestronglysuggests chemotherapy is the most common approach to ex- that RUNX2 plays a vital role in tumor initiation, tend the survival time of pancreatic cancer patients. progression, invasion and metastasis. From the clinical For advanced pancreatic cancer patients, a deoxycyti- point of view, the elevated expression level of RUNX2 dine analogue termed gemcitabine (GEM) (2′,2′- has been shown to correlate to poor prognosis of pa- difluorodeoxycytidine) has been considered to be the tients with pancreatic cancer or with thyroid cancer first choice as a front-line chemotherapy based on the [12, 13]. In support of these observations, it has been results of the Phase III trial [26, 27]. The cytotoxicity described that RUNX2 regulates numerous genes im- of GEM relies on its ability to promote cancer cell plicated in carcinogenesis including MMP9 death. Similar to the related nucleoside analog termed (matrixmetalloproteinase-9), MMP13 (matrixmetallo- cytarabine (Ara-C) [28], GEM is taken up within pan- proteinase-13),VEGF (vascular endothelial growth fac- creatic cancer cells through equilibrative nucleoside tor) and survivin [14–16]. Furthermore, Pratap et al. transporter-1 (hENT1) [29], and subjected to deoxycy- found that RUNX2 promotes invasion of bone tidine kinase (dCK)-mediated phosphorylation to be- metastatic cancer cells through the induction of come an active form (dFdCTP). dFdCTP is then MMP9, and also stimulates the early events of breast incorporated at the end of the elongating DNA cancer progression [17, 18]. Recently, we have de- strand, terminates DNA replication process, and scribed for the first time that siRNA-mediated knock- thereby inducing DNA fragmentation (cancer cell down of RUNX2 increases adriamycin (ADR) death) [30]. In addition to the advanced pancreatic sensitivity of p53-wild-type osteosarcoma cells cancer, GEM is also utilized to treat patients with the through the activation of p53 family-dependent cell other serious diseases such as non-small-lung cell, death pathway [19, 20]. Our subsequent studies breast, bladder, gastric and ovarian cancers. However, revealed that depletion of RUNX2 improves GEM theresponserateofGEMmonotherapyislowand sensitivity of pancreatic cancer cells regardless of their the improvement of 5-year survival rate is unsatisfied p53 status [21–23]. (less than 6 months) [31].TheefficacyofGEMisless In this review article, we provide a brief overview of than 20% of treated patients, and almost all the pa- the molecular basis behind drug-resistant phenotype of tients eventually become resistant to GEM [31]. pancreatic cancer cells, and also describe p53 family- Subsequently, the extensive studies to improve the un- dependent cell death pathway in response to DNA dam- favorable clinical outcome of the advanced pancreatic age. Subsequently, we summarize the current under- cancer patients by GEM-based combination
Load more

Recommended publications
  • Jdp2 Downregulates Trp53 Transcription to Promote Leukaemogenesis in the Context of Trp53 Heterozygosity
    Oncogene (2013) 32, 397 --402 & 2013 Macmillan Publishers Limited All rights reserved 0950-9232/13 www.nature.com/onc SHORT COMMUNICATION Jdp2 downregulates Trp53 transcription to promote leukaemogenesis in the context of Trp53 heterozygosity L van der Weyden1, AG Rust1,4, RE McIntyre1,4, CD Robles-Espinoza1, M del Castillo Velasco-Herrera1, R Strogantsev2, AC Ferguson-Smith2, S McCarthy1, TM Keane1, MJ Arends3 and DJ Adams1 We performed a genetic screen in mice to identify candidate genes that are associated with leukaemogenesis in the context of Trp53 heterozygosity. To do this we generated Trp53 heterozygous mice carrying the T2/Onc transposon and SB11 transposase alleles to allow transposon-mediated insertional mutagenesis to occur. From the resulting leukaemias/lymphomas that developed in these mice, we identified nine loci that are potentially associated with tumour formation in the context of Trp53 heterozygosity, including AB041803 and the Jun dimerization protein 2 (Jdp2). We show that Jdp2 transcriptionally regulates the Trp53 promoter, via an atypical AP-1 site, and that Jdp2 expression negatively regulates Trp53 expression levels. This study is the first to identify a genetic mechanism for tumour formation in the context of Trp53 heterozygosity. Oncogene (2013) 32, 397--402; doi:10.1038/onc.2012.56; published online 27 February 2012 Keywords: p53; Jdp2; transposon; heterozygosity; lymphoma; mice INTRODUCTION targeted by transposon insertion events leading to upregulated Genetic alterations of TP53 are frequent events in tumourigenesis Jdp2 expression and a decrease in Trp53 expression levels. Further and promote genomic instability, impair apoptosis, and contribute we illustrate that Jdp2 regulates the Trp53 promoter via an atypical to aberrant self-renewal.1--4 The spectrum of mutations that occur AP-1 binding site.
    [Show full text]
  • A Dissertation Entitled the Androgen Receptor
    A Dissertation entitled The Androgen Receptor as a Transcriptional Co-activator: Implications in the Growth and Progression of Prostate Cancer By Mesfin Gonit Submitted to the Graduate Faculty as partial fulfillment of the requirements for the PhD Degree in Biomedical science Dr. Manohar Ratnam, Committee Chair Dr. Lirim Shemshedini, Committee Member Dr. Robert Trumbly, Committee Member Dr. Edwin Sanchez, Committee Member Dr. Beata Lecka -Czernik, Committee Member Dr. Patricia R. Komuniecki, Dean College of Graduate Studies The University of Toledo August 2011 Copyright 2011, Mesfin Gonit This document is copyrighted material. Under copyright law, no parts of this document may be reproduced without the expressed permission of the author. An Abstract of The Androgen Receptor as a Transcriptional Co-activator: Implications in the Growth and Progression of Prostate Cancer By Mesfin Gonit As partial fulfillment of the requirements for the PhD Degree in Biomedical science The University of Toledo August 2011 Prostate cancer depends on the androgen receptor (AR) for growth and survival even in the absence of androgen. In the classical models of gene activation by AR, ligand activated AR signals through binding to the androgen response elements (AREs) in the target gene promoter/enhancer. In the present study the role of AREs in the androgen- independent transcriptional signaling was investigated using LP50 cells, derived from parental LNCaP cells through extended passage in vitro. LP50 cells reflected the signature gene overexpression profile of advanced clinical prostate tumors. The growth of LP50 cells was profoundly dependent on nuclear localized AR but was independent of androgen. Nevertheless, in these cells AR was unable to bind to AREs in the absence of androgen.
    [Show full text]
  • Regulation of Runx2 Accumulation and Its Consequences
    Regulation of Runx2 Accumulation and Its Consequences Junko Shimazu Submitted in partial fulfillment of the requirement for the degree of Doctor of Philosophy in the Graduate School of Arts and Sciences COLUMBIA UNIVERSITY 2016 ©2016 Junko Shimazu All Rights Reserved ABSTRACT Regulation of Runx2 Accumulation and Its Consequences Junko Shimazu Osteoblasts are bone-forming cells and therefore they are responsible of the synthesis of type I collagen, the main component of bone matrix. However, there is an apparent disconnect between the regulation of osteoblast differentiation and bone formation since the synthesis of Type I collagen precedes the expression of Runx2, the earliest determinant of osteoblast differentiation. Recently, genetic experiments in the mouse have revealed the existence of an unexpected cross-regulation between bone and other organs. In particular this body of work has highlighted the importance of osteoblasts as endocrine cells to regulate whole-body glucose homeostasis by secretion of a hormone, osteocalcin. However, the fundamental question of why bone regulates glucose homeostasis remained to be answered. Therefore, in my thesis, considering that bone is a metabolically demanding organ that constantly renews itself, I hypothesized that characterizing the connection between the need of glucose as a main nutrient in osteoblasts and bone development will provide a key to deeper understanding of why bone regulates glucose homeostasis. My work shows here that glucose uptake through GLUT1 in osteoblasts is needed for osteoblast differentiation by suppressing the AMPK-dependent activation by phosphorylation at S148 of Smurf1 that targets Runx2 for degradation. I also uncovered the mechanism of action of Smurf1 in this setting.
    [Show full text]
  • Effects of Estrogen Receptor and Wnt Signaling Activation On
    International Journal of Molecular Sciences Article Effects of Estrogen Receptor and Wnt Signaling Activation on Mechanically Induced Bone Formation in a Mouse Model of Postmenopausal Bone Loss 1, , 1, 1 1 Astrid Liedert * y, Claudia Nemitz y, Melanie Haffner-Luntzer , Fabian Schick , Franz Jakob 2 and Anita Ignatius 1 1 Institute of Orhopedic Research and Biomechanics, Trauma Research Center Ulm, University Medical Center Ulm, 89081 Ulm, Germany; [email protected] (C.N.); melanie.haff[email protected] (M.H.-L.); [email protected] (F.S.); [email protected] (A.I.) 2 Orthopaedic Center for Musculoskeletal Research, University of Würzburg, 97074 Würzburg, Germany; [email protected] * Correspondence: [email protected]; Tel.: +49-731-500-55333; Fax: +49-731-500-55302 These authors contributed equally to the study. y Received: 14 September 2020; Accepted: 31 October 2020; Published: 5 November 2020 Abstract: In the adult skeleton, bone remodeling is required to replace damaged bone and functionally adapt bone mass and structure according to the mechanical requirements. It is regulated by multiple endocrine and paracrine factors, including hormones and growth factors, which interact in a coordinated manner. Because the response of bone to mechanical signals is dependent on functional estrogen receptor (ER) and Wnt/β-catenin signaling and is impaired in postmenopausal osteoporosis by estrogen deficiency, it is of paramount importance to elucidate the underlying mechanisms as a basis for the development of new strategies in the treatment of osteoporosis. The present study aimed to investigate the effectiveness of the activation of the ligand-dependent ER and the Wnt/β-catenin signal transduction pathways on mechanically induced bone formation using ovariectomized mice as a model of postmenopausal bone loss.
    [Show full text]
  • Supplementary Information
    Osa et al Supplementary Information Clinical implications of monitoring nivolumab immunokinetics in previously treated non– small cell lung cancer patients Akio Osa, Takeshi Uenami, Shohei Koyama, Kosuke Fujimoto, Daisuke Okuzaki, Takayuki Takimoto, Haruhiko Hirata, Yukihiro Yano, Soichiro Yokota, Yuhei Kinehara, Yujiro Naito, Tomoyuki Otsuka, Masaki Kanazu, Muneyoshi Kuroyama, Masanari Hamaguchi, Taro Koba, Yu Futami, Mikako Ishijima, Yasuhiko Suga, Yuki Akazawa, Hirotomo Machiyama, Kota Iwahori, Hyota Takamatsu, Izumi Nagatomo, Yoshito Takeda, Hiroshi Kida, Esra A. Akbay, Peter S. Hammerman, Kwok-kin Wong, Glenn Dranoff, Masahide Mori, Takashi Kijima, Atsushi Kumanogoh Supplemental Figures 1 – 8 1 Osa et al Supplemental Figure 1. The frequency of nivolumab-bound T cells was maintained in patients who continued treatment. Nivolumab binding in CD8 and CD4 T cells was analyzed at two follow-up points, as indicated, in fresh peripheral blood from three representative cases from protocol 1 that continued treatment. 2 Osa et al Supplemental Figure 2. Long-term follow-up of nivolumab binding to T cells from fresh whole blood. Nivolumab binding was followed up in fresh peripheral blood from an additional case, Pt.7. 3 Osa et al Supplemental Figure 3. Long-term duration of nivolumab binding is due to sustained circulation of residual nivolumab in plasma. (A) PBMCs acquired from Pt.8 and 9 at pretreatment (pre PBMCs) and after a single dose (post 1 PBMCs) were cultured in regular medium without nivolumab (top and middle). Pre PBMCs were also incubated with 10 µg/ml nivolumab in vitro before the cultures were started (bottom). Nivolumab binding status was monitored at the indicated time points.
    [Show full text]
  • RUNX2 Regulates Leukemic Cell Metabolism and Chemotaxis in High-Risk T Cell Acute Lymphoblastic Leukemia
    RUNX2 regulates leukemic cell metabolism and chemotaxis in high-risk T cell acute lymphoblastic leukemia Filip Matthijssens, … , Pieter Van Vlierberghe, Ksenia Matlawska-Wasowska J Clin Invest. 2021;131(6):e141566. https://doi.org/10.1172/JCI141566. Research Article Oncology Graphical abstract Find the latest version: https://jci.me/141566/pdf The Journal of Clinical Investigation RESEARCH ARTICLE RUNX2 regulates leukemic cell metabolism and chemotaxis in high-risk T cell acute lymphoblastic leukemia Filip Matthijssens,1,2 Nitesh D. Sharma,3,4 Monique Nysus,3,4 Christian K. Nickl,3,4 Huining Kang,4,5 Dominique R. Perez,4,6 Beatrice Lintermans,1,2 Wouter Van Loocke,1,2 Juliette Roels,1,2 Sofie Peirs,1,2 Lisa Demoen,1,2 Tim Pieters,1,2 Lindy Reunes,1,2 Tim Lammens,2,7 Barbara De Moerloose,2,7 Filip Van Nieuwerburgh,8 Dieter L. Deforce,8 Laurence C. Cheung,9,10 Rishi S. Kotecha,9,10 Martijn D.P. Risseeuw,2,11 Serge Van Calenbergh,2,11 Takeshi Takarada,12 Yukio Yoneda,13 Frederik W. van Delft,14 Richard B. Lock,15 Seth D. Merkley,5 Alexandre Chigaev,4,6 Larry A. Sklar,4,6 Charles G. Mullighan,16 Mignon L. Loh,17 Stuart S. Winter,18 Stephen P. Hunger,19 Steven Goossens,1,2,20 Eliseo F. Castillo,5 Wojciech Ornatowski,21 Pieter Van Vlierberghe,1,2 and Ksenia Matlawska-Wasowska3,4 1Department of Biomolecular Medicine, Ghent University, Ghent, Belgium. 2Cancer Research Institute Ghent (CRIG), Ghent, Belgium. 3Department of Pediatrics, Division of Hematology-Oncology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA.
    [Show full text]
  • BMP9 Prevents Induction of Osteopontin in JNK-Inactivated
    International Journal of Biochemistry and Cell Biology 116 (2019) 105614 Contents lists available at ScienceDirect International Journal of Biochemistry and Cell Biology journal homepage: www.elsevier.com/locate/biocel BMP9 prevents induction of osteopontin in JNK-inactivated osteoblasts via Hey1-Id4 interaction T ⁎ Joji Kusuyamaa,b, , Changhwan Seonga,c, Toshiaki Nakamurad, Tomokazu Ohnishia, Muhammad Subhan Amira,c,e, Kaori Shimaf, Ichiro Sembaf, Kazuyuki Noguchid, Tetsuya Matsuguchia a Department of Oral Biochemistry, Field of Developmental Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan b Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Department of Medicine, Harvard Medical School, One Joslin Place, Boston, MA, 02215, USA c Department of Oral and Maxillofacial Surgery, Field of Oral and Maxillofacial Rehabilitation, Kagoshima University Graduate School of Medical and Dental Sciences, 8- 35-1 Sakuragaoka, Kagoshima, 890-8544, Japan d Department of Periodontology, Field of Oral and Maxillofacial Rehabilitation, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan e Department of Oral and Maxillofacial Surgery, Faculty of Dentistry, Airlangga University, Campus A UNAIR, JL. Mayjen Professor Doktor Moestopo No. 47, Pacar Kembang, Tambaksari, Kota SBY, Surabaya, Jawa Timur, 60132, Indonesia f Department of Oral Pathology, Field of Oncology, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan ARTICLE INFO ABSTRACT Keywords: Osteopontin (OPN) is an osteoblast-derived secretory protein that plays a role in bone remodeling, osteoblast BMP9 responsiveness, and inflammation. We recently found that osteoblast differentiation is type-specific, with con- Osteopontin ditions of JNK inactivation inducing osteoblasts that preferentially express OPN (OPN-type).
    [Show full text]
  • The Role of P53-Induced Mir-145A in Senescence and Osteogenesis of Mesenchymal Stem Cells
    The Role of p53-induced miR-145a in Senescence and Osteogenesis of Mesenchymal Stem Cells Chao Xia Shanghai Jiaotong University School of Medicine Xinhua Hospital Tianyuan Jiang Shanghai Jiaotong University School of Medicine Xinhua Hospital Yonghui Wang Shanghai Jiaotong University School of Medicine Xinhua Hospital Xiaoting Chen Shanghai Jiaotong University School of Medicine Xinhua Hospital Yan Hu Shanghai Jiaotong University School of Medicine Xinhua Hospital Yanhong Gao ( [email protected] ) https://orcid.org/0000-0003-4173-4855 Research Keywords: microRNAs, osteogenesis, senescence, mesenchymal stem cells, p53, Cbfb Posted Date: March 17th, 2020 DOI: https://doi.org/10.21203/rs.3.rs-17497/v1 License: This work is licensed under a Creative Commons Attribution 4.0 International License. Read Full License Page 1/21 Abstract Background: The osteogenic differentiation capacity of senescent bone marrow mesenchymal stem cells (MSCs) is diminished. However, little is known about the mechanisms. p53 not only regulates cellular senescence but also, as a negative regulator, is involved in bone formation. This study investigated the molecular mechanism of p53 in cellular senescence and osteogenesis. Methods: The expression of p53 and its downstream gene p21 were measured during cellular senescence and osteogenesis differentiation of primary bone marrow MSCs. Then miR-145a was picked out from those p53-induced miRNAs as its expression change in bone marrow MSCs senescence and osteogenesis induced by H2O2 and BMP-9, respectively. The function of p53 induced miR-145a was analyzed by transfected with miRNA mimic in osteogenic differentiation of MSCs. Western blot and luciferase reporter assay were used for validating the target of miR-145a.
    [Show full text]
  • Estrogen Promotes Mandibular Condylar Fibrocartilage
    www.nature.com/scientificreports OPEN Estrogen Promotes Mandibular Condylar Fibrocartilage Chondrogenesis and Inhibits Received: 27 November 2017 Accepted: 18 May 2018 Degeneration via Estrogen Published: xx xx xxxx Receptor Alpha in Female Mice Jennifer L. Robinson 1,3, Paola Soria2, Manshan Xu2, Mark Vrana1, Jefrey Luchetti1, Helen H. Lu3, Jing Chen2 & Sunil Wadhwa2 Temporomandibular joint degenerative disease (TMJ-DD) is a chronic form of TMJ disorder that specifcally aficts people over the age of 40 and targets women at a higher rate than men. Prevalence of TMJ-DD in this population suggests that estrogen loss plays a role in the disease pathogenesis. Thus, the goal of the present study was to determine the role of estrogen on chondrogenesis and homeostasis via estrogen receptor alpha (ERα) during growth and maturity of the joint. Young and mature WT and ERαKO female mice were subjected to ovariectomy procedures and then given placebo or estradiol treatment. The efect of estrogen via ERα on fbrocartilage morphology, matrix production, and protease activity was assessed. In the young mice, estrogen via ERα promoted mandibular condylar fbrocartilage chondrogenesis partly by inhibiting the canonical Wnt signaling pathway through upregulation of sclerostin (Sost). In the mature mice, protease activity was partly inhibited with estrogen treatment via the upregulation and activity of protease inhibitor 15 (Pi15) and alpha-2- macroglobulin (A2m). The results from this work provide a mechanistic understanding of estradiol on TMJ growth and homeostasis and can be utilized for development of therapeutic targets to promote regeneration and inhibit degeneration of the mandibular condylar fbrocartilage. Temporomandibular joint degenerative disease (TMJ-DD) is marked by degradation and premature calcifcation of the extracellular matrix (ECM) of the articular mandibular condylar fbrocartilage.
    [Show full text]
  • Identification of Shared and Unique Gene Families Associated with Oral
    International Journal of Oral Science (2017) 9, 104–109 OPEN www.nature.com/ijos ORIGINAL ARTICLE Identification of shared and unique gene families associated with oral clefts Noriko Funato and Masataka Nakamura Oral clefts, the most frequent congenital birth defects in humans, are multifactorial disorders caused by genetic and environmental factors. Epidemiological studies point to different etiologies underlying the oral cleft phenotypes, cleft lip (CL), CL and/or palate (CL/P) and cleft palate (CP). More than 350 genes have syndromic and/or nonsyndromic oral cleft associations in humans. Although genes related to genetic disorders associated with oral cleft phenotypes are known, a gap between detecting these associations and interpretation of their biological importance has remained. Here, using a gene ontology analysis approach, we grouped these candidate genes on the basis of different functional categories to gain insight into the genetic etiology of oral clefts. We identified different genetic profiles and found correlations between the functions of gene products and oral cleft phenotypes. Our results indicate inherent differences in the genetic etiologies that underlie oral cleft phenotypes and support epidemiological evidence that genes associated with CL/P are both developmentally and genetically different from CP only, incomplete CP, and submucous CP. The epidemiological differences among cleft phenotypes may reflect differences in the underlying genetic causes. Understanding the different causative etiologies of oral clefts is
    [Show full text]
  • Retinoblastoma Binding Protein-1 (RBP1) Is a Runx2 Coactivator and Promotes Osteoblastic Differentiation BMC Musculo- Skeletal Disorders 2010, 11:104
    Monroe et al. BMC Musculoskeletal Disorders 2010, 11:104 http://www.biomedcentral.com/1471-2474/11/104 RESEARCH ARTICLE Open Access RetinoblastomaResearch article binding protein-1 (RBP1) is a Runx2 coactivator and promotes osteoblastic differentiation David G Monroe*, John R Hawse, Malayannan Subramaniam and Thomas C Spelsberg Abstract Background: Numerous transcription factors are involved in the establishment and maintenance of the osteoblastic phenotype, such as Runx2, osterix and Dlx5. The transcription factor retinoblastoma binding protein-1 (RBP1) was recently identified as an estrogen regulated gene in an osteosarcoma cell model. Since the function of RBP1 in osteoblastic differentiation and mineralization is unknown, we investigated the role of RBP1 in these processes. Methods: To create a cell model with suppressed RBP1 expression, primary calvarial osteoblasts were infected with a shRNA lentiviral vector specific for mouse RBP1 (CalOB-ΔRBP1) or a scrambled control shRNA lentivirus (CalOB-Control). Stable cell lines were generated and their mineralization potential was determined using osteoblastic differentiation medium, Alizarin Red staining, and quantitative PCR (QPCR) analyses. Runx2 coactivation by RBP1 was determined through the use of transient transfection assays. Results: Stable expression of the RBP1 shRNA lentivirus in CalOB-ΔRBP1 cells resulted in a 65-70% suppression of RBP1 expression. Osteoblastic mineralization assays demonstrated that suppression of RBP1 results in a potent delay in osteoblastic nodule formation in the CalOB-ΔRBP1 cells with a concomitant decrease in the expression of the osteogenic transcription factors Runx2 and osterix, along with decreases in BMP2, alkaline phosphatase, osteocalcin and bone sialoprotein. Regulation of Runx2 expression by RBP1 was shown to be mediated through the proximal P2 Runx2 promoter.
    [Show full text]
  • The Multifaceted Output of C-Jun Biological Activity: Focus at the Junction of CD8 T Cell Activation and Exhaustion
    cells Review The Multifaceted Output of c-Jun Biological Activity: Focus at the Junction of CD8 T Cell Activation and Exhaustion Athanasios G. Papavassiliou 1 and Anna Maria Musti 2,* 1 Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; [email protected] 2 Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy * Correspondence: [email protected]; Tel.: +39-3337543732 Received: 22 September 2020; Accepted: 11 November 2020; Published: 13 November 2020 Abstract: c-Jun is a major component of the dimeric transcription factor activator protein-1 (AP-1), a paradigm for transcriptional response to extracellular signaling, whose components are basic-Leucine Zipper (bZIP) transcription factors of the Jun, Fos, activating transcription factor (ATF), ATF-like (BATF) and Jun dimerization protein 2 (JDP2) gene families. Extracellular signals regulate c-Jun/AP-1 activity at multiple levels, including transcriptional and posttranscriptional regulation of c-Jun expression and transactivity, in turn, establishing the magnitude and the duration of c-Jun/AP-1 activation. Another important level of c-Jun/AP-1 regulation is due to the capability of Jun family members to bind DNA as a heterodimer with every other member of the AP-1 family, and to interact with other classes of transcription factors, thereby acquiring the potential to integrate diverse extrinsic and intrinsic signals into combinatorial regulation of gene expression. Here, we review how these features of c-Jun/AP-1 regulation underlie the multifaceted output of c-Jun biological activity, eliciting quite distinct cellular responses, such as neoplastic transformation, differentiation and apoptosis, in different cell types.
    [Show full text]