Publications by authors named "Deniz Ozturk"

15 Publications

  • Page 1 of 1

MITF-MIR211 axis is a novel autophagy amplifier system during cellular stress.

Autophagy 2019 03 16;15(3):375-390. Epub 2018 Oct 16.

a Sabanci University , Faculty of Engineering and Natural Sciences, Molecular Biology, Genetics and Bioengineering Program , Orhanli-Tuzla , Turkey.

Macroautophagy (autophagy) is an evolutionarily conserved recycling and stress response mechanism. Active at basal levels in eukaryotes, autophagy is upregulated under stress providing cells with building blocks such as amino acids. A lysosome-integrated sensor system composed of RRAG GTPases and MTOR complex 1 (MTORC1) regulates lysosome biogenesis and autophagy in response to amino acid availability. Stress-mediated inhibition of MTORC1 results in the dephosphorylation and nuclear translocation of the TFE/MITF family of transcriptional factors, and triggers an autophagy- and lysosomal-related gene transcription program. The role of family members TFEB and TFE3 have been studied in detail, but the importance of MITF proteins in autophagy regulation is not clear so far. Here we introduce for the first time a specific role for MITF in autophagy control that involves upregulation of MIR211. We show that, under stress conditions including starvation and MTOR inhibition, a MITF-MIR211 axis constitutes a novel feed-forward loop that controls autophagic activity in cells. Direct targeting of the MTORC2 component RICTOR by MIR211 led to the inhibition of the MTORC1 pathway, further stimulating MITF translocation to the nucleus and completing an autophagy amplification loop. In line with a ubiquitous function, MITF and MIR211 were co-expressed in all tested cell lines and human tissues, and the effects on autophagy were observed in a cell-type independent manner. Thus, our study provides direct evidence that MITF has rate-limiting and specific functions in autophagy regulation. Collectively, the MITF-MIR211 axis constitutes a novel and universal autophagy amplification system that sustains autophagic activity under stress conditions. Abbreviations: ACTB: actin beta; AKT: AKT serine/threonine kinase; AKT1S1/PRAS40: AKT1 substrate 1; AMPK: AMP-activated protein kinase; ATG: autophagy-related; BECN1: beclin 1; DEPTOR: DEP domain containing MTOR interacting protein; GABARAP: GABA type A receptor-associated protein; HIF1A: hypoxia inducible factor 1 subunit alpha; LAMP1: lysosomal associated membrane protein 1; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MAPKAP1/SIN1: mitogen-activated protein kinase associated protein 1; MITF: melanogenesis associated transcription factor; MLST8: MTOR associated protein, LST8 homolog; MRE: miRNA response element; MTOR: mechanistic target of rapamycin kinase; MTORC1: MTOR complex 1; MTORC2: MTOR complex 2; PRR5/Protor 1: proline rich 5; PRR5L/Protor 2: proline rich 5 like; RACK1: receptor for activated C kinase 1; RPTOR: regulatory associated protein of MTOR complex 1; RICTOR: RPTOR independent companion of MTOR complex 2; RPS6KB/p70S6K: ribosomal protein S6 kinase; RT-qPCR: quantitative reverse transcription-polymerase chain reaction; SQSTM1: sequestosome 1; STK11/LKB1: serine/threonine kinase 11; TFE3: transcription factor binding to IGHM enhancer 3; TFEB: transcription factor EB; TSC1/2: TSC complex subunit 1/2; ULK1: unc-51 like autophagy activating kinase 1; UVRAG: UV radiation resistance associated; VIM: vimentin; VPS11: VPS11, CORVET/HOPS core subunit; VPS18: VPS18, CORVET/HOPS core subunit; WIPI1: WD repeat domain, phosphoinositide interacting 1.
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http://dx.doi.org/10.1080/15548627.2018.1531197DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6351134PMC
March 2019

The effect of unilateral forced nostril breathing on sleep in healthy right-handed men: a preliminary report.

Sleep Breath 2018 09 1;22(3):769-772. Epub 2018 Mar 1.

Department of Pulmonary Diseases, Ataturk University School of Medicine, 25240, Erzurum, Turkey.

Purpose: Although we spend about one-third of our lives in sleep and recognize its necessity for good health, sleep has only been partially elucidated in the last century. The nasal cycle of congestion and decongestion during sleep has various effects on human physiology. The aim of the present study was to investigate the effect of unilateral forced nostril breathing on sleep.

Methods: Twenty-one healthy male volunteers aged 18-24 years were included in the study. Only individuals with right-hand dominance were included. Subjects were observed during sleep for three nights under different conditions: no obstruction (normal sleep) on the first night, right nasal obstruction on the second night, and left nasal obstruction on the third night.

Results: The main findings of our study are that sleep efficiency, NREM stage III, and total sleep duration were greater during left nasal obstruction (right nostril dominant respiration), while apnea-hypopnea index (AHI), frequency of periodic limb movements, and oxygen desaturation were higher during right nasal obstruction (left nostril dominant respiration).

Conclusion: The nasal cycle has a significant impact on sleep which is reflected in sleep recordings. Our result supports that nasal obstructions, due to deviations, concha hypertrophy, or congestion/decongestion, might affect the physiology of respiration and sleep. Nasal obstruction should be taken into consideration when evaluating patients in sleep laboratories and further studies are required to elucidate the situation in the patients with nasal obstruction.
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http://dx.doi.org/10.1007/s11325-018-1648-0DOI Listing
September 2018

Cloning of Autophagy-Related MicroRNAs.

Methods Mol Biol 2019 ;1854:131-146

Faculty of Engineering and Natural Sciences, Molecular Biology, Genetics and Bioengineering Program, Sabanci University, Orhanli-Tuzla, Istanbul, 34956, Turkey.

Autophagy is a cellular survival pathway that is necessary for the degradation of cellular constituents such as long-lived proteins and damaged organelles. Conditions resulting in cellular stress such as starvation or hypoxia might activate autophagy. Being at the crossroads of various cellular response pathways, dysregulation of autophagy might result in pathological states including cancer and neurodegenerative diseases. Autophagy has also been shown to participate in stemness. MicroRNAs were introduced as novel regulators of autophagy, and accumulating results underlined the fact that they constituted an important layer of biological control mechanism on the autophagic activity.MicroRNAs are protein noncoding small RNAs that control cellular levels of transcripts and proteins through posttrancriptional mechanisms. Novel miRNAs in human and mouse genomes are yet to be identified. Considering the emerging role of autophagy in health and disease, identification of novel autophagy-regulating miRNAs and determination of relations between miRNA expression and physiological and pathological conditions might contribute to a better understanding of mechanisms governing health and disease. High-throughput techniques were developed for miRNA profiling, yet for a thorough characterization and miRNA target determination, miRNA cloning remains as an important step. Here, we describe a modified miRNA cloning method for the characterization of novel autophagy-regulating miRNAs.
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http://dx.doi.org/10.1007/7651_2017_83DOI Listing
June 2019

Autophagy-Regulating microRNAs and Cancer.

Front Oncol 2017 18;7:65. Epub 2017 Apr 18.

Molecular Biology, Genetics and Bioengineering Program, Faculty of Engineering and Natural Sciences, Sabanci University, Istanbul, Turkey.

Macroautophagy (autophagy herein) is a cellular stress response and a survival pathway that is responsible for the degradation of long-lived proteins, protein aggregates, as well as damaged organelles in order to maintain cellular homeostasis. Consequently, abnormalities of autophagy are associated with a number of diseases, including Alzheimers's disease, Parkinson's disease, and cancer. According to the current view, autophagy seems to serve as a tumor suppressor in the early phases of cancer formation, yet in later phases, autophagy may support and/or facilitate tumor growth, spread, and contribute to treatment resistance. Therefore, autophagy is considered as a stage-dependent dual player in cancer. microRNAs (miRNAs) are endogenous non-coding small RNAs that negatively regulate gene expression at a post-transcriptional level. miRNAs control several fundamental biological processes, and autophagy is no exception. Furthermore, accumulating data in the literature indicate that dysregulation of miRNA expression contribute to the mechanisms of cancer formation, invasion, metastasis, and affect responses to chemotherapy or radiotherapy. Therefore, considering the importance of autophagy for cancer biology, study of autophagy-regulating miRNA in cancer will allow a better understanding of malignancies and lead to the development of novel disease markers and therapeutic strategies. The potential to provide study of some of these cancer-related miRNAs were also implicated in autophagy regulation. In this review, we will focus on autophagy, miRNA, and cancer connection, and discuss its implications for cancer biology and cancer treatment.
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http://dx.doi.org/10.3389/fonc.2017.00065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5394422PMC
April 2017

The effect of the application of manual pressure before the administration of intramuscular injections on students' perceptions of postinjection pain: a semi-experimental study.

J Clin Nurs 2017 Jun 24;26(11-12):1632-1638. Epub 2016 Nov 24.

Department of Nursing, Fundamentals of Nursing, Faculty of Health Science, Gazi University, Ankara, Turkey.

Aims And Objectives: To evaluate the efficacy of applying manual pressure before intramuscular injection and compare it with the standard injection technique in terms of reducing the young adult student's postinjection pain.

Background: The administration of intramuscular injections is a procedure performed by nurses and one that causes anxiety and pain for the patient. Nurses have ethical and legal obligations to mitigate injection-related pain and the nurses' use of effective pain management not only provides physical comfort to the patients, but also improves the patients' experience.

Design: Comparative experimental study.

Methods: This study was conducted with first-year university students (n = 123) who were scheduled for hepatitis A and hepatitis B vaccination via deltoid muscle injection. Students were randomly assigned to the groups. Comparison group students (n = 60) were given an injection using the conventional method, that is without manual pressure being applied prior to the injection. The experimental group students (n = 63) received manual pressure at the vaccination site immediately before injection for a period of 10 seconds. The two techniques were used randomly. The subjects were given pressure to the injection site, and perceived pain intensity was measured using Numerical Rating Scale.

Results: Findings demonstrate that students experienced significantly less pain when they received injections with manual pressure compared with the standard injection technique. The postinjection average pain score in the comparison group was higher than that in the experimental group (p < 0·05).

Conclusions: This study's results show that the application of manual pressure to the injection site before intramuscular injections reduces postinjection pain intensity in young adult students (p < 0·05). Based on these results before the injection, applying manual pressure to the adult's intramuscular injection site is recommended.

Relevance To Clinical Practice: Applying pressure to the injection area is a simple and cost-effective method to reduce the pain associated with injection.
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http://dx.doi.org/10.1111/jocn.13530DOI Listing
June 2017

Highly luminescent and cytocompatible cationic Ag2S NIR-emitting quantum dots for optical imaging and gene transfection.

Nanoscale 2015 Jul;7(26):11352-62

Koc University, Graduate School of Materials Science and Engineering, Rumelifeneri Yolu, Sarıyer, 34450, Istanbul, Turkey.

The development of non-toxic theranostic nanoparticles capable of delivering a therapeutic cargo and providing a means for diagnosis is one of the most challenging tasks in nano-biotechnology. Gene therapy is a very important mode of therapy and polyethyleneimine (PEI) is one of the most successful vehicles for gene transfection, yet poses significant toxicity. Optical imaging utilizing quantum dots is one of the newer but fast growing diagnostic modalities, which requires non-toxic, highly luminescent materials, preferentially active in the near infrared region. Ag2S NIRQDs fit to this profile perfectly. Here, we demonstrate the aqueous synthesis of cationic Ag2S NIRQDs with a mixed coating of 2-mercaptopropionic acid (2MPA) and PEI (branched, 25 kDa), which are highly luminescent in the NIR-I window (λem = 810-840 nm) as new theranostic nanoparticles. Synergistic stabilization of the QD surface via the simultaneous use of a small molecule and a polymeric material provided the highest quantum yield, 150% (with respect to LDS 798 at pH 7.4), reported in the literature for Ag2S. These cationic particles show a dramatic improvement in cytocompatibility even without PEGylation, a strong optical signal easily detected by confocal laser microscopy and effective conjugation and transfection of the green fluorescence protein plasmid (pGFP) to HeLa and MCF-7 cell lines (40% efficiency). Overall, these Ag2S NIRQDs show great potential as new theranostics.
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http://dx.doi.org/10.1039/c5nr00189gDOI Listing
July 2015

A longitudınal study on the effect of tailored training and counseling on the professional attitude of nursing students.

J Prof Nurs 2015 May-Jun;31(3):262-70. Epub 2014 Oct 23.

Department of Nursing, Faculty of Health Science, Gazi University, Ankara, Turkey.. Electronic address:

The development of professional attitudes in nursing students is influenced by their learning experiences (knowledge, skills, and attitudes) and instructors' professional behaviors. Instructors can enhance students' professional attitude by organizing the training environment, being a role model, and providing counseling. This study was conducted as a tailoring intervention study over 4 years (2010-2013) examining 73 nursing students (34 intervention, 39 control) to determine the effect of training and counseling on nursing students' professional attitudes. Data were collected utilizing the Introductory Characteristics Form and the Instrument of Professional Attitude for Student Nurses. Intervention group students were provided training and counseling complementing their current education to develop their professional attitudes. Controls proceeded with their current education. Instrument for Professional Attitude for Student Nurses posttest scores of the intervention group were significantly higher than those of control group students. Furthermore, intervention group scores on all subscales other than "competence and continuous education" significantly increased after training. Controls showed no growth in professional attitudes, other than in "contribution to scientific knowledge." The training and counseling program had a positive influence on the professional attitudes of nursing students. Thus, providing tailored training and counseling associated to professionalism throughout the educational process at schools providing nursing training is recommended.
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http://dx.doi.org/10.1016/j.profnurs.2014.10.004DOI Listing
January 2017

Influence of vascular normalization on interstitial flow and delivery of liposomes in tumors.

Phys Med Biol 2015 Feb 22;60(4):1477-96. Epub 2015 Jan 22.

Department of Physics, Bogazici University, 34342 Bebek, Istanbul, Turkey. Center for Life Sciences and Technologies, Bogazici University, 34342 Bebek, Istanbul, Turkey.

Elevated interstitial fluid pressure is one of the barriers of drug delivery in solid tumors. Recent studies have shown that normalization of tumor vasculature by anti-angiogenic factors may improve the delivery of conventional cytotoxic drugs, possibly by increasing blood flow, decreasing interstitial fluid pressure, and enhancing the convective transvascular transport of drug molecules. Delivery of large therapeutic agents such as nanoparticles and liposomes might also benefit from normalization therapy since their transport depends primarily on convection. In this study, a mathematical model is presented to provide supporting evidence that normalization therapy may improve the delivery of 100 nm liposomes into solid tumors, by both increasing the total drug extravasation and providing a more homogeneous drug distribution within the tumor. However these beneficial effects largely depend on tumor size and are stronger for tumors within a certain size range. It is shown that this size effect may persist under different microenvironmental conditions and for tumors with irregular margins or heterogeneous blood supply.
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http://dx.doi.org/10.1088/0031-9155/60/4/1477DOI Listing
February 2015

Determining the effect of periodic training on the basic psychomotor skills of nursing students.

Nurse Educ Today 2015 Feb 8;35(2):402-7. Epub 2014 Nov 8.

Department of Nursing and Health Services, Faculty of Health Science, Nuh Naci Yazgan University, Turkey. Electronic address:

Background: Basic psychomotor skill training starts in the first year in nursing education. The psychomotor skills taught in the first year of nursing training constitute a foundation for all professional practices. Conducting periodic training for skills with which students are deficient can support mastery learning.

Objectives: The study was conducted as an interventional study for determining the effect of periodic training on the basic psychomotor skills learned in the Fundamentals of Nursing course.

Design: The sample consisted of 70 students attending the Fundamentals of Nursing course at nursing students in a university in Ankara, over 4 years between 2010 and 2013.

Methods: The study was conducted as an interventional study for a period of 4 years. The data were collected through a questionnaire that was applied 4 times at the end of each academic year. According to the results of the forms evaluated at the end of each year, 4 additional laboratory activities were conducted addressing the deficient psychomotor skills of students at the beginning of the new academic semester in the 2nd and 3rd years. In the 4th-year clinic practice, courses were arranged to practice still deficient psychomotor skills.

Results: It was determined that students practiced nearly all of the basic psychomotor skills during clinical practice and that the practices with which they felt themselves to be inadequate gradually decreased following periodic training; this decrease was significant (p<0.05). While the number of students who could practice was low at the first measurement, following 3 years of periodic training, these skills increased significantly (p<0.05).

Conclusion: This study determined that periodic training addressing the deficient psychomotor skills of nursing students was effective. We recommend that students' psychomotor skills be evaluated periodically and repetitive training based on the results of this evaluation be provided throughout the undergraduate nursing education process.
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http://dx.doi.org/10.1016/j.nedt.2014.10.023DOI Listing
February 2015

MIR376A is a regulator of starvation-induced autophagy.

PLoS One 2013 16;8(12):e82556. Epub 2013 Dec 16.

Faculty of Engineering and Natural Sciences, Sabanci University, Istanbul, Turkey.

Background: Autophagy is a vesicular trafficking process responsible for the degradation of long-lived, misfolded or abnormal proteins, as well as damaged or surplus organelles. Abnormalities of the autophagic activity may result in the accumulation of protein aggregates, organelle dysfunction, and autophagy disorders were associated with various diseases. Hence, mechanisms of autophagy regulation are under exploration.

Methods: Over-expression of hsa-miR-376a1 (shortly MIR376A) was performed to evaluate its effects on autophagy. Autophagy-related targets of the miRNA were predicted using Microcosm Targets and MIRanda bioinformatics tools and experimentally validated. Endogenous miRNA was blocked using antagomirs and the effects on target expression and autophagy were analyzed. Luciferase tests were performed to confirm that 3' UTR sequences in target genes were functional. Differential expression of MIR376A and the related MIR376B was compared using TaqMan quantitative PCR.

Results: Here, we demonstrated that, a microRNA (miRNA) from the DLK1/GTL2 gene cluster, MIR376A, played an important role in autophagy regulation. We showed that, amino acid and serum starvation-induced autophagy was blocked by MIR376A overexpression in MCF-7 and Huh7 cells. MIR376A shared the same seed sequence and had overlapping targets with MIR376B, and similarly blocked the expression of key autophagy proteins ATG4C and BECN1 (Beclin 1). Indeed, 3' UTR sequences in the mRNA of these autophagy proteins were responsive to MIR376A in luciferase assays. Antagomir tests showed that, endogenous MIR376A was participating to the control of ATG4C and BECN1 transcript and protein levels. Moreover, blockage of endogenous MIR376A accelerated starvation-induced autophagic activity. Interestingly, MIR376A and MIR376B levels were increased with different kinetics in response to starvation stress and tissue-specific level differences were also observed, pointing out to an overlapping but miRNA-specific biological role.

Conclusions: Our findings underline the importance of miRNAs encoded by the DLK1/GTL2 gene cluster in stress-response control mechanisms, and introduce MIR376A as a new regulator of autophagy.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0082556PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3864973PMC
September 2014

Effect of web-based education on nursing students' urinary catheterization knowledge and skills.

Nurse Educ Today 2014 May 20;34(5):802-8. Epub 2013 Aug 20.

Hacettepe University, Faculty of Nursing, 06100 Ankara, Turkey. Electronic address:

Background: Nursing is a practice-based discipline that requires the integration of theory and practice. Nurse educators must continuously revise educational curricula and incorporate information technology into the curriculum to provide students with the necessary knowledge and skills.

Objectives: The aim of this study was to assess the effect of web-based education on students' urinary catheterization knowledge and skills.

Design: A convenience sample of 111 first year nursing students enrolled at two universities in Ankara during the academic year of 2011-2012 participated in this quasi-experimental study.

Method: The experimental group (n=59) received a web-based and web-enhanced learning approach along with learning and practicing the required material twice as much as the control group, whereas the control group (n=52) received traditional classroom instruction. A knowledge test of 20 multiple-choice questions and a skills checklist were used to assess student performance.

Results: There was no difference between the experimental group and the control group in knowledge scores; however, students in the web-based group had higher scores for urinary catheterization skills. The highest scores in knowledge and skills were obtained by students who experienced web-based education as a supplement to tradition instruction.

Conclusion: Web-based education had positive effects on the urinary catheterization skills of nursing students, and its positive effect increased for both knowledge and skills when it supplements classroom instruction. Based on these results, we suggest the use of web-based education as a supplement to traditional classroom instruction for nursing education.
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http://dx.doi.org/10.1016/j.nedt.2013.08.007DOI Listing
May 2014

MIR181A regulates starvation- and rapamycin-induced autophagy through targeting of ATG5.

Autophagy 2013 Mar 15;9(3):374-85. Epub 2013 Jan 15.

Faculty of Engineering and Natural Sciences, Biological Sciences and Bioengineering Program, Sabanci University, Istanbul, Turkey.

Macroautophagy (autophagy herein) is a cellular catabolic mechanism activated in response to stress conditions including starvation, hypoxia and misfolded protein accumulation. Abnormalities in autophagy were associated with pathologies including cancer and neurodegenerative diseases. Hence, elucidation of the signaling pathways controlling autophagy is of utmost importance. Recently we and others described microRNAs (miRNAs) as novel and potent modulators of the autophagic activity. Here, we describe MIR181A (hsa-miR-181a-1) as a new autophagy-regulating miRNA. We showed that overexpression of MIR181A resulted in the attenuation of starvation- and rapamycin-induced autophagy in MCF-7, Huh-7 and K562 cells. Moreover, antagomir-mediated inactivation of endogenous miRNA activity stimulated autophagy. We identified ATG5 as an MIR181A target. Indeed, ATG5 cellular levels were decreased in cells upon MIR181A overexpression and increased following the introduction of antagomirs. More importantly, overexpression of ATG5 from a miRNA-insensitive cDNA construct rescued autophagic activity in the presence of MIR181A. We also showed that the ATG5 3' UTR contained functional MIR181A responsive sequences sensitive to point mutations. Therefore, MIR181A is a novel and important regulator of autophagy and ATG5 is a rate-limiting miRNA target in this effect.
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http://dx.doi.org/10.4161/auto.23117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3590257PMC
March 2013

A case with vesicouterine fistula: mini review.

Arch Gynecol Obstet 2012 Mar 8;285(3):667-70. Epub 2012 Jan 8.

Köyceğiz State Hospital, Gelişim Mah. Köyceğiz, 48800 Muğla, Turkey.

Aim: The objective is to present a case with vesicouterine fistula after cesarean section.

Case: A 27-year-old female patient, G2P2, was admitted to hospital with the complaint of severe crampy pelvic pain and dysuria during micturition without any incontinence. She had two cesarean sections, last was 14 months before admission. Her urinalysis revealed microscopic hematuria. Diagnosis of uterovesical fistula suspected by transvaginal ultrasonography and diagnosed by hysterography. Vesicouterine fistula operated by transperitoneal approach without any complication.

Conclusion: Increasing cesarean section rates concomitantly carries increasing maternal and neonatal adverse outcomes including operative complications as genitourinary fistulae.
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http://dx.doi.org/10.1007/s00404-011-2188-zDOI Listing
March 2012

The crosstalk of RAS with the TGF-β family during carcinoma progression and its implications for targeted cancer therapy.

Curr Cancer Drug Targets 2010 Dec;10(8):849-57

Department of Medicine I, Division, Institute of Cancer Research, Medical University of Vienna, Borschke-Gasse 8a, A-1090 Vienna, Austria.

Both RAS and transforming growth factor (TGF)-β signaling cascades are central in tumorigenesis and show synergisms depending on tumor stage and tissue context. In this review we focus on the interaction of RAS subeffector proteins with signaling components of the TGF-β family including those of TGF-βs, activins and bone morphogenic proteins. Compelling evidence indicates that RAS signaling is essentially involved in the switch from tumor-suppressive to tumor-promoting functions of the TGF-β family leading to enhanced cancer growth and metastatic dissemination of primary tumors. Thus, the interface of these signaling cascades is considered as a promising target for the development of novel cancer therapeutics. The current pharmacological anti-cancer concepts combating the molecular cooperation between RAS and TGF-β family signaling during carcinoma progression are critically discussed.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3044462PMC
http://dx.doi.org/10.2174/156800910793357943DOI Listing
December 2010

Activins and follistatins: Emerging roles in liver physiology and cancer.

World J Hepatol 2009 Oct;1(1):17-27

Emanuel Kreidl, Deniz Öztürk, Thomas Metzner, Walter Berger, Michael Grusch, Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, Borschkegasse 8a, Vienna A-1090, Austria.

Activins are secreted proteins belonging to the TGF-β family of signaling molecules. Activin signals are crucial for differentiation and regulation of cell proliferation and apoptosis in multiple tissues. Signal transduction by activins relies mainly on the Smad pathway, although the importance of crosstalk with additional pathways is increasingly being recognized. Activin signals are kept in balance by antagonists at multiple levels of the signaling cascade. Among these, follistatin and FLRG, two members of the emerging family of follistatin-like proteins, can bind secreted activins with high affinity, thereby blocking their access to cell surface-anchored activin receptors. In the liver, activin A is a major negative regulator of hepatocyte proliferation and can induce apoptosis. The functions of other activins expressed by hepatocytes have yet to be more clearly defined. Deregulated expression of activins and follistatin has been implicated in hepatic diseases including inflammation, fibrosis, liver failure and primary cancer. In particular, increased follistatin levels have been found in the circulation and in the tumor tissue of patients suffering from hepatocellular carcinoma as well as in animal models of liver cancer. It has been argued that up-regulation of follistatin protects neoplastic hepatocytes from activin-mediated growth inhibition and apoptosis. The use of follistatin as biomarker for liver tumor development is impeded, however, due to the presence of elevated follistatin levels already during preceding stages of liver disease. The current article summarizes our evolving understanding of the multi-faceted activities of activins and follistatins in liver physiology and cancer.
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http://dx.doi.org/10.4254/wjh.v1.i1.17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2999257PMC
October 2009