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A porphobilinogen deaminase (PBGD) Ran-binding protein interaction is implicated in nuclear trafficking of PBGD in differentiating glioma cells

Abstract

Porphobilinogen deaminase (PBGD) is a rate-limiting enzyme of the heme biosynthesis pathway, whose level is elevated in various human tumors. PBGD was observed in both nuclear and cytoplasmic fractions of C6 glioma cells by immunostaining. During mitosis, chromatids were intensely stained for PBGD in comparison to the interphase chromatin. Using the yeast two-hybrid system, we identified RanBPM, the nuclear Ran-binding protein, as an interacting partner of PBGD. During butyrate-induced differentiation of C6, both nuclear and cytoplasmic PBGD levels declined as did Ran protein and its nucleotide exchange factor RCC1. N,N′-hexamethylene bis-acetamide-dependent differentiation resulted in an increase of the cytoplasmic PBGD, whereas nuclear PBGD, Ran protein and RCC1 remained unchanged. mRNA levels of PBGD remained unchanged during stimulation with both butyrate and N,N′-hexamethylene bis-acetamide. The enzymatic activity of PBGD and protoporphyrin IX synthesis in C6 cells were dependent on the differentiation induction agent. We conclude that PBGD possibly has a nuclear role in addition to its cytosolic enzymatic activity required for heme synthesis, which is related to cell transformation and differentiation.

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Acknowledgements

We thank HemeBiotech, Denmark for the generous gift of anti-human PBGD antibodies. We are grateful to Dr Takeharu Nishimoto, Kyushu University, Japan for the generous gift of anti-human RanBPM antibodies. Thanks to Ms Judith Hanania for her skilful help during the execution of this study. This study was supported by a GIF Grant no. 052-202.08/98.

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Correspondence to Zvi Malik.

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Greenbaum, L., Katcoff, D., Dou, H. et al. A porphobilinogen deaminase (PBGD) Ran-binding protein interaction is implicated in nuclear trafficking of PBGD in differentiating glioma cells. Oncogene 22, 5221–5228 (2003). https://doi.org/10.1038/sj.onc.1206723

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Keywords

  • PBGD
  • nuclear-localization
  • RanBPM
  • porphyrin

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