Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

GATA4 is a regulator of astrocyte cell proliferation and apoptosis in the human and murine central nervous system

Oncogene volume 28, pages 3033–3046 (2009)Cite this article

Abstract

The GATA transcription factors consist of six family members, which bind to the consensus DNA-binding element, W- GATA-R, and are poorly characterized in the central nervous system (CNS). Using retroviral gene trapping on transgenic mouse glioma models, we identified GATA6 to be a novel tumor suppressor gene in glioblastoma multiforme. We now show GATA4, a family member of GATA6, to be expressed in the neurons and glia of normal murine and human embryonic and adult CNS. Silencing GATA4 in normal astrocytes did not alter their growth properties. In contrast, knockdown of Gata4 in p53 null non-transformed murine astrocytes induced transformation, with increased proliferation and resistance to chemotherapy or radiation-induced apoptosis. Furthermore, GATA4 expression was lost in a panel of human malignant astrocytoma cell lines. GATA4 overexpression in normal human and murine astrocytes resulted in a cell cycle block in G1 phase, with increased apoptosis. Mechanistically, GATA4 was a transcriptional inducer of the cyclin-dependent kinase inhibitor, p15INK4B, leading to the attenuation of cyclin D1. GATA4 expression was also induced by transforming growth factor-β, leading to the inhibition of astrocyte proliferation. Collectively, we show that GATA4 is expressed in the embryonic and adult CNS and acts as a negative regulator of astrocyte proliferation and growth.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

Abbreviations

CNS:

central nervous system

IHC:

immunohistochemistry

NHA:

normal human astrocytes

NMA:

normal murine astrocytes

IF:

immunofluoresence cytochemistry

GBM:

glioblastoma multiforme

References

  • Afouda BA, Ciau-Uitz A, Patient R . (2005). GATA4, 5 and 6 mediate TGFbeta maintenance of endodermal gene expression in Xenopus embryos. Development 132: 763–774.

    Article  CAS  Google Scholar 

  • Anttonen M, Parviainen H, Kyronlahti A, Bielinska M, Wilson DB, Ritvos O et al. (2006). GATA-4 is a granulosa cell factor employed in inhibin-alpha activation by the TGF-beta pathway. J Mol Endocrinol 36: 557–568.

    Article  CAS  Google Scholar 

  • Belaguli NS, Zhang M, Rigi M, Aftab M, Berger DH . (2007). Cooperation between GATA4 and TGF-beta signaling regulates intestinal epithelial gene expression. Am J Physiol Gastrointest Liver Physiol 292: G1520–G1533.

    Article  CAS  Google Scholar 

  • Bogler O, Nagane M, Gillis J, Huang HJ, Cavenee WK . (1999). Malignant transformation of p53-deficient astrocytes is modulated by environmental cues in vitro. Cell Growth Differ 10: 73–86.

    CAS  PubMed  Google Scholar 

  • Cantor AB, Orkin SH . (2002). Transcriptional regulation of erythropoiesis: an affair involving multiple partners. Oncogene 21: 3368–3376.

    Article  CAS  Google Scholar 

  • Capo-chichi CD, Roland IH, Vanderveer L, Bao R, Yamagata T, Hirai H et al. (2003). Anomalous expression of epithelial differentiation-determining GATA factors in ovarian tumorigenesis. Cancer Res 63: 4967–4977.

    CAS  PubMed  Google Scholar 

  • Caslini C, Capo-chichi CD, Roland IH, Nicolas E, Yeung AT, Xu XX . (2006). Histone modifications silence the GATA transcription factor genes in ovarian cancer. Oncogene 25: 5446–5461.

    Article  CAS  Google Scholar 

  • Garg V, Kathiriya IS, Barnes R, Schluterman MK, King IN, Butler CA et al. (2003). GATA4 mutations cause human congenital heart defects and reveal an interaction with TBX5. Nature 424: 443–447.

    Article  CAS  Google Scholar 

  • Guo M, Akiyama Y, House MG, Hooker CM, Heath E, Gabrielson E et al. (2004). Hypermethylation of the GATA genes in lung cancer. Clin Cancer Res 10: 7917–7924.

    Article  CAS  Google Scholar 

  • Guo M, House MG, Akiyama Y, Qi Y, Capagna D, Harmon J et al. (2006). Hypermethylation of the GATA gene family in esophageal cancer. Int J Cancer 119: 2078–2083.

    Article  CAS  Google Scholar 

  • Hannon GJ, Beach D . (1994). p15INK4B is a potential effector of TGF-beta-induced cell cycle arrest. Nature 371: 257–261.

    Article  CAS  Google Scholar 

  • Kamnasaran D, Guha A . (2005). Expression of GATA6 in the human and mouse central nervous system. Brain Res Dev Brain Res 160: 90–95.

    Article  CAS  Google Scholar 

  • Kamnasaran D, Qian B, Hawkins C, Stanford WL, Guha A . (2007). GATA6 is an astrocytoma tumor suppressor gene identified by gene trapping of mouse glioma model. Proc Natl Acad Sci USA 104: 8053–8058.

    Article  CAS  Google Scholar 

  • Kobayashi S, Lackey T, Huang Y, Bisping E, Pu WT, Boxer LM et al. (2006). Transcription factor gata4 regulates cardiac BCL2 gene expression in vitro and in vivo. FASEB J 20: 800–802.

    Article  CAS  Google Scholar 

  • Koutsourakis M, Langeveld A, Patient R, Beddington R, Grosveld F . (1999). The transcription factor GATA6 is essential for early extraembryonic development. Development 126: 723–732.

    CAS  PubMed  Google Scholar 

  • Kuo CT, Morrisey EE, Anandappa R, Sigrist K, Lu MM, Parmacek MS et al. (1997). GATA4 transcription factor is required for ventral morphogenesis and heart tube formation. Genes Dev 11: 1048–1060.

    Article  CAS  Google Scholar 

  • Lawson MA, Buhain AR, Jovenal JC, Mellon PL . (1998). Multiple factors interacting at the GATA sites of the gonadotropin-releasing hormone neuron-specific enhancer regulate gene expression. Mol Endocrinol 12: 364–377.

    Article  CAS  Google Scholar 

  • Lawson MA, Mellon PL . (1998). Expression of GATA-4 in migrating gonadotropin-releasing neurons of the developing mouse. Mol Cell Endocrinol 140: 157–161.

    Article  CAS  Google Scholar 

  • Lowry JA, Atchley WR . (2000). Molecular evolution of the GATA family of transcription factors: conservation within the DNA-binding domain. J Mol Evol 50: 103–115.

    Article  CAS  Google Scholar 

  • Luo Y, Fischer FR, Hancock WW, Dorf ME . (2000). Macrophage inflammatory protein-2 and KC induce chemokine production by mouse astrocytes. J Immunol 165: 4015–4023.

    Article  CAS  Google Scholar 

  • Morrisey EE, Tang Z, Sigrist K, Lu MM, Jiang F, Ip HS et al. (1998). GATA6 regulates HNF4 and is required for differentiation of visceral endoderm in the mouse embryo. Genes Dev 12: 3579–3590.

    Article  CAS  Google Scholar 

  • Patient RK, McGhee JD . (2002). The GATA family (vertebrates and invertebrates). Curr Opin Genet Dev 12: 416–422.

    Article  CAS  Google Scholar 

  • Perlman H, Suzuki E, Simonson M, Smith RC, Walsh K . (1998). GATA-6 induces p21(Cip1) expression and G1 cell cycle arrest. J Biol Chem 273: 13713–13718.

    Article  CAS  Google Scholar 

  • Quelle DE, Ashmun RA, Hannon GJ, Rehberger PA, Trono D, Richter KH et al. (1995). Cloning and characterization of murine p16INK4a and p15INK4b genes. Oncogene 11: 635–645.

    CAS  Google Scholar 

  • Ray A, Ho M, Ma J, Parkes RK, Mainprize TG, Ueda S et al. (2004). A clinicobiological model predicting survival in medulloblastoma. Clin Cancer Res 10: 7613–7620.

    Article  CAS  Google Scholar 

  • Reamon-Buettner SM, Cho SH, Borlak J . (2007). Mutations in the 3′-untranslated region of GATA4 as molecular hotspots for congenital heart disease (CHD). BMC Med Genet 8: 38.

    Article  Google Scholar 

  • Reilly KM, Loisel DA, Bronson RT, McLaughlin ME, Jacks T . (2000). Nf1;Trp53 mutant mice develop glioblastoma with evidence of strain-specific effects. Nat Genet 26: 109–113.

    Article  CAS  Google Scholar 

  • Rempe DA, Lelli KM, Vangeison G, Johnson RS, Federoff HJ . (2007). In cultured astrocytes, p53 and MDM2 do not alter hypoxia-inducible factor-1alpha function regardless of the presence of DNA damage. J Biol Chem 282: 16187–16201.

    Article  CAS  Google Scholar 

  • Rich JN, Zhang M, Datto MB, Bigner DD, Wang XF . (1999). Transforming growth factor-beta-mediated p15(INK4B) induction and growth inhibition in astrocytes is SMAD3-dependent and a pathway prominently altered in human glioma cell lines. J Biol Chem 274: 35053–35058.

    Article  CAS  Google Scholar 

  • Setogawa T, Shinozaki-Yabana S, Masuda T, Matsuura K, Akiyama T . (2006). The tumor suppressor LKB1 induces p21 expression in collaboration with LMO4, GATA-6, and Ldb1. Biochem Biophys Res Commun 343: 1186–1190.

    Article  CAS  Google Scholar 

  • Shang Y, Myers M, Brown M . (2002). Formation of the androgen receptor transcription complex. Mol Cell 9: 601–610.

    Article  CAS  Google Scholar 

  • Sonoda Y, Ozawa T, Hirose Y, Aldape KD, McMahon M, Berger MS et al. (2001). Formation of intracranial tumors by genetically modified human astrocytes defines four pathways critical in the development of human anaplastic astrocytoma. Cancer Res 61: 4956–4960.

    CAS  PubMed  Google Scholar 

  • Temple S . (2001). The development of neural stem cells. Nature 414: 112–117.

    Article  CAS  Google Scholar 

  • Wada H, Hasegawa K, Morimoto T, Kakita T, Yanazume T, Abe M et al. (2002). Calcineurin-GATA-6 pathway is involved in smooth muscle-specific transcription. J Cell Biol 156: 983–991.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

SA was supported by a RESTRACOMP studentship award from the Hospital for Sick Children and an Ontario Institute of Cancer Research award. Thanks to Dr Deepak Kamnasaran for technical advice and Jing Ma for technical assistance on IHC. AG was funded for this study by the National Cancer Institute of Canada, Brain Tumor Society and National Brain Tumor Foundation.

Author information

Authors and Affiliations

  1. The Arthur and Sonia Labatt's Brain Tumor Research Centre, The Hospital for Sick Children's Research Institute, University of Toronto, Toronto, Ontario, Canada

    S Agnihotri, A Wolf, D Picard & A Guha

  2. Division of Pathology, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada

    C Hawkins

  3. Division of Neurosurgery, Toronto Western Hospital, University of Toronto, Toronto, Ontario, Canada

    A Guha

Authors
  1. S Agnihotri
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A Wolf
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. D Picard
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. C Hawkins
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. A Guha
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to A Guha.

Additional information

Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Agnihotri, S., Wolf, A., Picard, D. et al. GATA4 is a regulator of astrocyte cell proliferation and apoptosis in the human and murine central nervous system. Oncogene 28, 3033–3046 (2009). https://doi.org/10.1038/onc.2009.159

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2009.159

Keywords

This article is cited by

Search

Advanced search

Quick links