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Minimal and inducible regulation of tissue factor pathway inhibitor-2 in human gliomas

Oncogene volume 21, pages 921–928 (2002)Cite this article

Abstract

Tissue factor pathway inhibitor-2 (TFPI-2), a serine protease inhibitor abundant in the extra cellular matrix, is highly expressed in non-invasive cells but undetectable levels in highly invasive human glioma cells. The mechanisms responsible for its transcriptional regulation are not well elucidated. In this study, we made several deletion constructs from a 3.6 kb genomic fragment from Hs683 cells containing the 5′-flanking region of the TFPI-2 gene, transiently transfected with these constructs into non-invasive (Hs683) and highly invasive (SNB19) human glioma cells, and assessed their expression by using a luciferase reporter gene. Three constructs showed high promoter activity (pTF5, −670 to +1; pTF6, −312 to +1; pTF2, −1511 to +1). Another construct, pTF8 (−81 to +1), showed no activity. PTF9, a variant of pTF5 in which a further 231 bp fragment (−312 to −81) was deleted, from the [−670 to +1] pTF5 region, also showed no promoter activity. Hence, (−312 to −81) this region is essential for the transcription of TFPI-2 in glioma cells. Sequencing of this promoter region revealed that it has a high G+C content, contains potential SP1 and AP1 binding motifs, and lacks canonical TATA and CAAT boxes immediately upstream of the major transcriptional initiation site, although CAAT boxes were found about −3000 bp upstream of the transcription start site. We also found a strong repressor in the region between −927 to –1181, upstream of the major transcriptional initiation site, followed by positive elements or enhancers between –1511 to −1181. These positive elements masked the silencer effect. Finally TFPI-2 was induced in Hs683 cells transfected with the pTF6 construct (−312 to +1) and stimulated with phorbol-12-myristate-13-acetate (PMA). We conclude that the −312 to +1 region is critical for the minimal and inducible regulation of TFPI-2 in non-invasive (Hs683) and highly invasive (SNB19) human glioma cell lines.

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Abbreviations

TFPI-2:

tissue factor pathway inhibitor-2

PMA:

phorbol myristate acetate

kb:

kilobase pair(s)

bp:

base pair(s)

PCR:

polymerase chain reaction

SP1:

stimulatory protein 1

AP1:

activator protein-1

NE:

nuclear extract

EMSA:

electrophoretic mobility shift assay

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Acknowledgements

The nucleotide sequence reported in this paper has been submitted to GenBank with accession number AF266279. Supported by National Cancer Institute grants, CA-76350, CA-75557 and CA75692 (to JS Rao) and HL-64119 (to W Kisiel).

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Authors and Affiliations

  1. Division of Cancer Biology, Department of Biomedical and Therapeutic Sciences, University of Illinois, Peoria, Illinois, USA

    Santhi D Konduri, Niranjan Yanamandra, Anastasia Tasiou & Jasti S Rao

  2. Department of Neurosurgery, University of Illinois, Peoria, Illinois, USA

    Dzung H Dinh, William C Olivero & Jasti S Rao

  3. Department of Neuro-pathology, University of Illinois, Peoria, Illinois, USA

    Meena Gujrati

  4. Department of Thoracic/Head and Neck Medical Oncology, The University of Texas, M.D. Anderson Cancer Center, Houston, Texas, USA

    Harish Srinivas

  5. Department of Neurosurgery, The University of Texas, M.D. Anderson Cancer Center, Houston, Texas, USA

    Francis Ali Osman

  6. Center for Prostate Disease Research, Rockville, Maryland, USA

    Chilukuri N Rao

  7. ZymoGenetics, Inc., Seattle, Washington, USA

    Donald C Foster

  8. University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA

    Walter Kisiel

  9. Department of Propedeutic Surgery, Athens University School of Medicine, Athens, Greece

    Gregory Kouraklis

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  1. Santhi D Konduri
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Correspondence to Chilukuri N Rao.

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Konduri, S., Osman, F., Rao, C. et al. Minimal and inducible regulation of tissue factor pathway inhibitor-2 in human gliomas. Oncogene 21, 921–928 (2002). https://doi.org/10.1038/sj.onc.1204983

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