Nuclear distribution of porphobilinogen deaminase (PBGD) in glioma cells: A regulatory role in cancer transformation?

L. Greenbaum, Y. Gozlan, D. Schwartz, D. J. Katcoff, Z. Malik

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

Abstract

Recently, considerable interest has been directed to red-fluorescence photodiagnosis of brain and other tumours during surgery using the protoporphyrin IX natural precursor, 5-aminolaevulinic acid. In the present study we focused on the role of the rate-limiting enzyme porphobilinogen deaminase in glioma C6 cell activity, differentiation and sub-cellular distribution. Over-expression of the human housekeeping porphobilinogen deaminase in the glioma cells, using the housekeeping-porphobilinogen deaminase plasmid, induced a GI cell cycle attenuation accompanied by increases in enzyme activity and c6 differentiation toward astrocytes. Visualisation of subcellular localisation of the porphobilinogen deaminase using the independent techniques of fluorescence immuno-staining with specific anti-human porphobilinogen deaminase antibodies and cellular expression of porphobilinogen deaminase fused to green fluorescent protein, revealed (unexpectedly) a major fraction of porphobilinogen deaminase in the nucleus and only a minor fraction in the cytoplasm. Both C and N terminals of porphobilinogen deaminase fused to green fluorescent protein revealed a major fraction of the newly synthesized fused porphobilinogen deaminase in the nucleus. Furthermore, newborn rat brain cells grown in a primary culture showed the same localisation pattern of porphobilinogen deaminase in the nuclei. Stimulation of C6 glioma cell differentiation by butyrate induced a marked decrease in porphobilinogen deaminase both in the nucleus and in the cytoplasm as determined by Western blotting and fluorescence immuno-localisation. These findings suggest a possible dual role for housekeeping porphobilinogen deaminase in fast dividing glioma cells, one related to the porphyrin synthesis pathway and another coupled to nuclear function, which might be linked to tumorigenesis.

Original languageEnglish
Pages (from-to)1006-1011
Number of pages6
JournalBritish Journal of Cancer
Volume86
Issue number6
DOIs
StatePublished - 18 Mar 2002

Bibliographical note

Funding Information:
We thank Hemebiotech, Denmark for the generous gift of antihuman PBGD antibodies. We are grateful to Ms Judith Hanania for her skilful help during the execution of this study and Professor N Schoenfeld, Dr R Mamet and R Mevasser of the Porphyria Reference Laboratory, The Rabin Center, Israel for their assistance. This study was supported by a GIF grant no. 052-202.08/98.

Keywords

  • Differentiation
  • Glioma c6
  • Porphobilinogen deaminase
  • Protoporphyrin

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