Skip Navigation

Cardiovascular Research 2001 50(1):3-6; doi:10.1016/S0008-6363(01)00218-8
© 2001 by European Society of Cardiology
This Article
Right arrow Extract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Flesch, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Flesch, M.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Copyright © 2001, European Society of Cardiology

On the trail of cardiac specific transcription factors

Markus Flesch*

Winters Center for Heart Failure Research, Baylor College of Medicine, VA Medical Center, Bldg. 110, 2002 Holcombe Blvd., Houston, TX 77030, USA

* Tel.: +1-713-794-7949; fax: +1-713-794-7770 mflesch{at}bcm.tmc.edu

accepted 7 February 2001

See article by Dellow et al. [1] (pages 24–33) in this issue.


   1 Introduction
Top
 1 Introduction
2 Sp transcription factor...
 3 GATA transcription factor...
 4 MEF2 transcription factor...
 5 HCB1 and HCB2...
 References
 
Transcription factors are the last link in signaling cascades regulating gene transcription. An increasing number of transcription factors have been described over the last years, and for many genes, essential transcription factor binding regions have been identified. The detailed understanding of the promoter regions essential for gene transcription and the different transcription factors, which are involved in promoter activation, is one of the scientific challenges of this decade and a prerequisite for targeted interventions in gene expression. In this context, the discovery of organ and gene specific transcription factors are of particular interest.

In this issue of Cardiovascular Research [1], the group of Paul J.R. Barton reports on recent progress in their efforts to define the essential activation sites of the human cardiac troponin I promoter. This promoter is interesting for cardiovascular research because troponin I is one of the few sarcomeric proteins, which are exclusively expressed in cardiac muscle. One might speculate that this promoter will be useful for the development of cardiac specific targeting vectors, which might be used in future gene therapy of cardiac muscle diseases. In a previous report Bhavsar et al. demonstrated that a minimal 98 bp containing promoter segment is sufficient to initiate human troponin I gene expression [2]. Within this compact region GATA-4, MEF2/Oct-1, Sp1 and CACC box-binding factors are required for optimal gene activation. These recent findings are in accordance with an earlier report by Di Lisi et al. [3] who demonstrated that binding sites specific for Sp1, MEF2/Oct-1 and GATA are necessary for activation of the mouse cardiac troponin I promoter. In this issue, Barton's group describes two potentially novel cardiac specific transcription factors, which bind to the CACC/Sp1-box element and seem to be essential for troponin I gene expression [1]. This editorial provides a short survey on recent findings concerning the involvement of Sp1, MEF2/Oct1 and GATA transcription factors in cardiac gene regulation before commenting on the recent discovery of the two potentially new transcription factors.


   2 Sp transcription factor family
Top
 1 Introduction
 2 Sp transcription factor...
3 GATA transcription factor...
 4 MEF2 transcription factor...
 5 HCB1 and HCB2...
 References
 
The four members of the Sp transcription factor family, Sp1, Sp2, Sp3 and Sp4, are characterized by a highly conserved DNA-binding domain composed of three zinc fingers close to the C-terminus and serine/threonine- and glutamine-rich domains in their N-terminal region. They bind to widely distributed promoter elements such as the GC-box (GGGGCGGGG) and the related GT/CACC-box (GGTGTGGGG). Due to the wide distribution of these promoter elements, Sp family transcription factors seem to be involved in the regulation of a large number of genes including housekeeping genes, tissue specific genes and cell cycle regulated genes. There is some evidence that these transcription factors may play an important role in developmental gene regulation [4]. The majority of Sp family members are regarded as activators of gene transcription. However Sp family transcription factors might also exert inhibitory effects on transcription, and this holds true especially for Sp3. The inhibitory effect of Sp3 might be due to the fact that Sp3 binds to the same promoter sites as Sp1 thereby suppressing Sp1 mediated promoter activation [5]. In this context, it has been suggested that the ratio between Sp1 and Sp3 might be important for activatory or inhibitory effects of these transcription factors [4]. Alternatively, glycosylation or phosphorylation of Sp proteins might alter their effect on promoter modulation [6,7].

There is increasing evidence that Sp1 is involved in the regulation of many cardiac genes. It has been demonstrated that SP1 binding sites are necessary to activate the {alpha}-cardiac actin promoter in a tissue specific manner [8] and that a Sp1 sequence acts as an {alpha}1-adrenergic response element in the atrial natriuretic factor and the {alpha}-actin promoter [9,10]. There is evidence that Sp1 promoter sites are essential for full sarcoplasmic reticulum Ca2+-ATPase (SERCA2) gene transcription in myocytes [11,12] and that enhanced binding of Sp1 and Sp3 to two GC box promoter elements contributes to gene transcription up-regulation of the rat Na,K-ATPase β1 subunit gene [13]. Also, Sp1 seems to be important for the regulation of genes involved in cardiac metabolism. Downregulation of Sp1 in neonatal and adult hearts goes along with a decreased gene transcription of the fast glucose transporter protein GLUT1, which is highest expressed during the late fetal life [14]. In accordance with this, Sp3 has been demonstrated to repress GLUT1 glucose transporter gene transcription in myoblasts and non-muscle cells [15]. Similarly, Sp1 and Sp3 might contribute to the downregulation of medium-chain acyl CoA-dehydrogenase, an enzyme which catalyzes a rate-limiting step in the myocardial fatty acid β-oxidation cycle. The downregulation of this enzyme during cardiac hypertrophy has been linked to increases in Sp1 and Sp3 [16]. Thus, there is evidence that Sp family transcription factors might be important in cardiac development and upregulated in cardiac hypertrophy and may contribute to reactivation of fetal gene expression patterns [16].

The precise mechanisms involved in the regulation of Sp family transcription factors in the heart remain to be elucidated. McDonough et al. [17] demonstrated that electrical pacing and overexpression of c-JUN terminal kinase synergistically activate Sp1, and they suggested that Sp1 might play a role in calcium-mediated transcriptional activation. Another stimulus leading to up-regulation of Sp1 is hypoxia as has been demonstrated in isolated human endothelial cells [18]. Thus, Sp family proteins seem to play a role in cardiac gene transcriptional regulation during the fetal stage and in response to myocardial stress stimuli including pressure overload, hypoxia or increases in intracellular calcium.


   3 GATA transcription factor family
Top
 1 Introduction
 2 Sp transcription factor...
 3 GATA transcription factor...
4 MEF2 transcription factor...
 5 HCB1 and HCB2...
 References
 
Members of the GATA family of transcription factors are zinc finger proteins, which have also been demonstrated to play a pivotal role for the regulation of cell growth and differentiation. The first three members of the family, GATA-1, -2 and -3 are restricted to hematopoietic cells and ectodermal derivatives. GATA-4, -5 and -6 are the transcription factors which are of functional relevance for the heart [19]. They are highly homologous in their amino acid sequence at their DNA binding sites, but differ outside the zinc finger region. Besides the heart, they are only expressed in the gut. GATA-4 is the predominant transcription factor in cardiac myocytes being present at all stages of cardiac development. GATA-6 is expressed in the precardiac mesoderm and is later found in cardiac myocytes and vascular smooth muscle cells. GATA-5 is mainly found in endocardial cells [19]

GATA-4, -5 and -6 bind to a consensus motif, which is highly preserved in a variety of cardiac gene promoters including atrial natriuretic factor [20], B-type natriuretic peptide [21], cardiac troponin C [22], slow myosin heavy chain [23] and the cardiac Na+–Ca2+-exchanger [24]. The important role of GATA-4 for cardiac development is demonstrated by the fact that deletion of this transcription factor prevents the formation of the pericardial cavity and the heart tube [25,26]. Similarly, GATA-4 is important for postnatal cardiac gene transcription where it is involved in the regulation of genes such as {alpha}-myosin heavy chain [27], myosin light chain 1 [28] and the angiotensin type I receptor [29]. There is evidence that GATA elements are essential for pressure overload induced upregulation of the AT1-receptor [29] and pressure overload and cytokine induced gene transcription for β-myosin heavy chain [30,31]. In the latter case, upregulation of GATA-5 in response to leukemia inhibitory factor stimulation of neonatal cardiac myocytes increased cardiac specific gene expression [31]. Involvement of GATA-4 and to a smaller extent also GATA-5 in myocardial hypertrophy is further supported by the finding that GATA elements play an important role in basal and phenylephrine induced endothelin-1 transcription in cardiac myocytes [32]. Interestingly, GATA-4 is phosphorylated in an ERK1/2-dependent manner in response to {alpha}1-adrenergic stimulation [32]. A pivotal role of GATA-4 in the hypertrophic process has been suggested based on the observation that GATA-4 binds to the transcription factor NF-AT3 and might thereby be linked to the calcineurin signal transduction pathway [33]. Only recently, it has been demonstrated that calcineurin-mediated nuclear translocation of NF-AT3 and increased GATA-4 expression is a mediator of pacing induced upregulation of the muscle specific mitochondrial energy metabolizing enzyme adenylsuccinate synthase 1 gene [34]. Similarly, the mitochondrial carnitine palmitoyltransferase I β (CPT-Iβ) gene transcription is driven synergistically by GATA-4 and serum response factor [35], indicating that also GATA-4 and cofactors may play an important role in regulating the transcription of genes involved in cardiac myocyte energy metabolism.


   4 MEF2 transcription factor family
Top
 1 Introduction
 2 Sp transcription factor...
 3 GATA transcription factor...
 4 MEF2 transcription factor...
5 HCB1 and HCB2...
 References
 
Members of the myocyte enhancer factor-2 family (MEF2) are transcription factors, which bind to a consensus DNA sequence (T/C)TA(A/T)4TA(G/A) present in many muscle and non-muscle gene promoters [36]. MEF2 binding sites have been described in the promoters of {alpha}-myosin heavy chain [37], cardiac troponin T [38], desmin [39] and as outlined above cardiac troponin I [3]. For activation of some of these promoters including the {alpha}-MHC gene, intact MEF2 binding sites seem to be essential [40]. However, the expression of other genes without MEF2 binding sites in their promoter regions including atrial natriuretic factor and {alpha}-cardiac actin also seem to depend on MEF2 proteins, since MEF2 deletion leads to a loss of these proteins in knockout embryos [40,36]. One potential mechanism by which MEF2 influences promoter activation in these genes is by interaction with other transcription factors such as GATA-4 thereby enhancing the transcriptional activity of this zinc-finger protein [36]. Similar observations have been made previously for the interaction of MEF2 proteins with myogenic basic helix-loop-helix (bHLH) proteins in skeletal muscle [41]. Hardly anything is known about the regulation of MEF2 in response to myocardial stress factors. There is evidence that the transcriptional activity of MEF2 is enhanced in response to p38 dependent phosphorylation [42] and that this pathway contributes to the involvement of MEF2 in cardiac hypertrophic gene regulation [43].


   5 HCB1 and HCB2 as potential new cardiac specific transcription factors
Top
 1 Introduction
 2 Sp transcription factor...
 3 GATA transcription factor...
 4 MEF2 transcription factor...
 5 HCB1 and HCB2...
References
 
In the current issue of Cardiovascular Research [1], evidence is provided for two new cardiac specific transcription factors, which bind to a common CACC-box/Sp1 element within the proximal 98 bp promoter region of the human cardiac troponin I gene. They are called HCB1 and HCB2 (for heart CACC-box binding factors). These transcription factors are not zinc finger proteins like GATA and SP family transcription factors. Moreover, there is evidence that they occur exclusively in cardiac muscle. Interestingly, they seem to be more important for promoter activation than the well characterized zinc finger proteins Sp1 and Sp3, which also bind to this promoter region.

The information provided on these new transcription factors is rather limited, and it is too early to arrange these newly discovered proteins in any order with other known transcription factors. As a matter of fact cloning and further characterization of HCB1 and HCB2 seem to be essential at this moment. It will have to be demonstrated whether they occur not only in fetal, but also in adult myocardium. In consequence, one wishes to know about the potential involvement of HCB1 and HCB2 in cardiac development as well as in hypertrophic cardiac gene expression. It might be interesting to know whether they interact with other transcription factors and, like MEF2, might affect the transcription of genes without HCB1/2 binding elements in their promoter regions. Finally, one may have to search for mutations in the CACC-box and the binding sites for HCB1 and HCB2 which may lead to cardiac hypertrophy as demonstrated for other mutations within the cardiac troponin I gene [44].

The present publication sets the stage for further research on the trail of cardiac specific transcription factors. Hopefully, the answers to these questions will better define the cardiac specific function of HCB1 and HCB2, which may be of potential use in the design of cardiac specific targeting vectors in the near future. Thus, the reader of this issue of Cardiovascular Research may be witness of an interesting step forward in our understanding how transcription of cardiac genes is specifically regulated.


   References
Top
 1 Introduction
 2 Sp transcription factor...
 3 GATA transcription factor...
 4 MEF2 transcription factor...
 5 HCB1 and HCB2...
 References
 

  1. Dellow K.A., Bhavsar P.K., Brand N.J., Barton P.J.R. Identification of novel, cardiac-restricted transcription factors binding to a CACC-box within the human cardiac troponin I promotor. Cardiovasc Res (2001) 50:24–33.[Abstract/Free Full Text]
  2. Bhavsar P.K., Dellow K.A., Yacoub M.H., et al. Identification of cis-acting DNA elements required for expression of the human cardiac troponin I gene promoter. J Mol Cell Cardiol (2000) 32:95–108.[CrossRef][ISI][Medline]
  3. Di Lisi R., Millino C., Calabria E., et al. Combinatorial cis-acting elements control tissue-specific activation of the cardiac troponin I gene in vitro and in vivo. J Biol Chem (1998) 273:25371–25380.[Abstract/Free Full Text]
  4. Suske G. The Sp-family of transcription factors. Gene (1999) 238:291–300.[CrossRef][ISI][Medline]
  5. Hagen G., Mueller S., Beato M., et al. Sp1-mediated transcriptional activation is repressed by Sp3. EMBO J (1994) 13:3843–3851.[ISI][Medline]
  6. Jackson S.P., MacDonald J.J., Lees-Miller S., et al. GC box binding induces phosphorylation of Sp1 by a DNA-dependent protein kinase. Cell (1990) 63:155–165.[CrossRef][ISI][Medline]
  7. Jackson S.P., Tjian R. O-Glycosylation of eukaryotic transcription factors: implications for mechanisms of transcriptional regulation. Cell (1988) 55:125–133.[CrossRef][ISI][Medline]
  8. Sartorelli V., Hong N.A., Bishopric N.H., et al. Myocardial activation of the human cardiac alpha-actin promoter by helix-loop-helix proteins. Proc Natl Acad Sci USA (1992) 89:4047–4051.[Abstract/Free Full Text]
  9. Ardati A., Nemer M. A nuclear pathway for {alpha}1-adrenergic receptor signaling in cardiac cells. EMBO J (1993) 12:5131–5139.[ISI][Medline]
  10. Karns L.R., Kariya K., Simpson P.C. M-CAT, CArG, and Sp1 elements are required for {alpha}1-adrenergic induction of the skeletal {alpha}-actin promoter during cardiac myocyte hypertrophy. Transcriptional enhancer factor-1 and protein kinase C as conserved transducers of the fetal program in cardiac growth. J Biol Chem (1995) 270:410–417.[Abstract/Free Full Text]
  11. Baker D.L., Dave V., Reed T., et al. Multiple Sp1 binding sites in the cardiac/slow twitch muscle sarcoplasmic reticulum Ca2+-ATPase gene promoter are required for expression in So18 muscle cells. J Biol Chem (1996) 271(10):5921–5928.[Abstract/Free Full Text]
  12. Wankerl M., Boheler K.R., Fiszman M.Y., et al. Molecular cloning and analysis of the human cardiac sarcoendoplasmic reticulum Ca2+-ATPase (SERCA) gene promoter. J Mol Cell Cardiol (1996) 28:2139–2150.[CrossRef][ISI][Medline]
  13. Santalucia T., Boheler K.R., Brand N.J., et al. Factors involved in GLUT-1 glucose transporter gene transcription in cardiac muscle. J Biol Chem (1999) 274:17626–17634.[Abstract/Free Full Text]
  14. Zhuang Y., Wendt C., Gick G. Regulation of Na,K-ATPase β1 subunit gene transcription by low external potassium in cardiac myocytes. Role of Sp1 and Sp3. J Biol Chem (2000) 275:24173–24184.[Abstract/Free Full Text]
  15. Fandos C., Sanchez-Feutrie M., Santalucia T., et al. GLUT1 glucose transporter gene transcription is repressed by Sp3. Evidence for a regulatory role of Sp3 during myogenesis. J Mol Biol (1999) 294:103–119.[CrossRef][ISI][Medline]
  16. Sack M.N., Disch D.L., Rockman H.A., et al. A role for Sp and nuclear receptor transcription factors in a cardiac hypertrophic growth program. Proc Nat Acad Sci USA (1997) 94:6438–6443.[Abstract/Free Full Text]
  17. McDonough P., Hanford D.S., Sprenkle A.B., et al. Collaborative roles for c-Jun N-terminal kinase, c-Jun, serum response factor and Sp1 in calcium-regulated myocardial gene expression. J Biol Chem (1997) 272:24046–24053.[Abstract/Free Full Text]
  18. Xu Q., Ji Y-S, Schmedtje J.F. Sp1 increases expression of cyclooxygenase-2 in hypoxic vascular endothelium. J Biol Chem (2000) 275:24583–24589.[Abstract/Free Full Text]
  19. Charron F., Nemer M. GATA transcription factors and cardiac development. Sem Cell Devel Biol (1999) 10:85–91.[CrossRef][ISI][Medline]
  20. Durocher D., Charron F., Warren R., et al. The cardiac transcription factors Nkx2-5 and GATA-4 are mutual cofactors. EMBO J (1997) 16:5687–5696.[CrossRef][ISI][Medline]
  21. Grepin C., Dagnino L., Robitaille L., et al. A hormone-encoding gene identifies a pathway for cardiac but not skeletal muscle gene transcription. Mol Cell Biol (1994) 14:3115–3129.[Abstract/Free Full Text]
  22. Ip H.S., Wilson D.B., Heikinheimo M., et al. The GATA-4 transcription factor transactivates the cardiac muscle-specific troponin C promoter–enhancer in nonmuscle cells. Mol Cell Biol (1994) 14:7517–7526.[Abstract/Free Full Text]
  23. Wang G.F., Nikovit W.J.R., Schleinitz M., et al. A positive GATA element and a negative vitamin D receptor like element control atrial chamber-specific expression of a slow myosin-heavy chain gene during cardiac morphogenesis. Mol Cell Biol (1998) 18:6023–6034.[Abstract/Free Full Text]
  24. Nicholas S.B., Philipson K.D. Cardiac expression of the Na+/Ca2+ exchanger NCX1 is GATA factor dependent. Am J Physiol (1999) 277:H324–H330.[ISI][Medline]
  25. Kuo C.T., Morrisey E.E., Anandappa R., et al. GATA4 transcription factor is required for ventral morphogenesis and heart tube formation. Genes Dev (1997) 11:1048–1060.[Abstract/Free Full Text]
  26. Molkentin J.D., Lin Q., Duncan S.A., et al. Requirement of the transcription factor GATA4 for heart tube formation and ventral morphogenesis. Genes Dev (1997) 11:1061–1072.[Abstract/Free Full Text]
  27. Molkentin J.D., Kalvakolanu D.V., Markham E. Transcription factor GATA-4 regulates cardiac muscle-specific expression of the {alpha}-myosin heavy-chain gene. Mol Cell Biol (1994) 14:4947–4957.[Abstract/Free Full Text]
  28. McGrew M.J., Bogdanova N., Hasegawa K., et al. Distinct gene expression patterns in skeletal and cardiac muscle are dependent on common regulatory sequences in the MLC1/3 locus. Mol Cell Biol (1996) 14:4947–4957.
  29. Herzig T.C., Jobe S.M., Aoki H., et al. Angiotensin II type1a receptor gene expression in the heart: AP1 and GATA-4 participate in the response to pressure overload. Proc Natl Acad Sci USA (1997) 94:7543–7548.[Abstract/Free Full Text]
  30. Hasegawa K., Le S.J., Jobe S.M., et al. cis-Acting sequences that mediate induction of β-myosin heavy chain gene expression during left ventricular hypertrophy due to aortic constriction. Circulation (1997) 96:3943–3953.[Abstract/Free Full Text]
  31. Morimoto T., Hasegawa K., Kaburagi S., et al. GATA-5 is involved in leukemia inhibitory factor-responsive transcription of the β-myosin heavy chain gene in cardiac myocytes. J Biol Chem (1999) 274:12811–12818.[Abstract/Free Full Text]
  32. Morimoto T., Hasegawa K., Kaburagi S., et al. Phosphorylation of GATA-4 is involved in {alpha}1-adrenergic agonist-responsive transcription of the endothelin-1 gene in cardiac myocytes. J Biol Chem (2000) 275:13721–13726.[Abstract/Free Full Text]
  33. Molkentin J.D., Lu J.R., Antos C.L., et al. A calcineurin-dependent transcriptional pathway for cardiac hypertrophy. Cell (1998) 93:215–228.[CrossRef][ISI][Medline]
  34. Xia Y., McMillin J.B., Lewis A., et al. Electrical stimulation of neonatal cardiac myocytes activates the NFAT3 and GATA4 pathways and up-regulates the adenylosuccinate synthetase 1 gene. J Biol Chem (2000) 275:1855–1863.[Abstract/Free Full Text]
  35. Moore M.L., Wang G-L, Belaguli N.S., et al. GATA-4 and serum response factor regulate transcription of the muscle-specific carnitin palmitoyltransferase I β in rat heart. J Biol Chem (2001) 276:1026–1033.[Abstract/Free Full Text]
  36. Morin S., Charron F., Robitaille L., et al. GATA-dependent recruitment of MEF1 proteins to target promoters. EMBO J (2000) 19:2046–2055.[CrossRef][ISI][Medline]
  37. Molkentin J.D., Markham B.E. Myocyte-specific enhancer-binding factor (MEF2) regulates {alpha}-cardiac myosin heavy chain gene expression in vitro and in vivo. J Biol Chem (1993) 268:19512–19520.[Abstract/Free Full Text]
  38. Wang Q., Sigmund C.D., Lin J.J. Identification of cis elements in the cardiac troponin T gene conferring specific expression in cardiac muscle of transgenic mice. Circ Res (2000) 86:478–484.[Abstract/Free Full Text]
  39. Kuisk I.R., Li H., Trans D., et al. A single MEF2 site governs desmin transcription in both heart and skeletal muscle during mouse embryogenesis. Dev Biol (1996) 174:1–13.[CrossRef][ISI][Medline]
  40. Lin Q., Schwary J., Bucan C., et al. Control of mouse cardiac morphogenesis and myogenesis by transcription factor MEF2c. Science (1997) 276:1404–1407.[Abstract/Free Full Text]
  41. Molkentin J.D., Black B.L., Martin J.F., et al. Cooperative activation of muscle gene expression by MEF2 and myogenic bHLH proteins. Cell (1995) 83:1125–1136.[CrossRef][ISI][Medline]
  42. Han J., Jiang Y., Li Z., et al. Activation of the transcription factor MEF2C by the MAPkinase p38 in inflammation. Nature (1997) 386:296–299.[CrossRef][Medline]
  43. Kolodziejczyk S.M., Wang L., Balazsi K., et al. MEF2 is upregulated during cardiac hypertrophy and is required for normal postnatal growth of the myocardium. Curr Biol (1999) 9:1203–1206.[CrossRef][ISI][Medline]
  44. Kimura A., Harada H., Park J.E., et al. Mutations in the cardiac troponin I gene associated with hypertrophic cardiomyopathy. Nat Genet (1997) 16:379–382.[CrossRef][ISI][Medline]

Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?



This Article
Right arrow Extract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Flesch, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Flesch, M.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?