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

Greenbaum, Lior; Katcoff, Don J.; Dou, Haoran; Gozlan, Yael; Malik, Zvi

doi:10.1038/sj.onc.1206723

Cited by 28 publications

(16 citation statements)

References 45 publications

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“…Decreased expression of PBGD mRNA in AD may be unrelated to heme biosynthesis. A “moonlighting” function for PBGD in the cell nucleus, which in glioma cells may be linked to tumorigenesis and cell cycle activity, has been reported [11, 12]. Moreover, 50% reduction in PBGD mRNA expression by itself may not significantly affect cerebral heme synthesis.…”

Section: Discussionmentioning

confidence: 99%

Down-regulation of aminolevulinate synthase, the rate-limiting enzyme for heme biosynthesis in Alzheimer's disease

Dwyer

Smith

Richardson

et al. 2009

Neuroscience Letters

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Heme is an essential cell metabolite, intracellular regulatory molecule, and protein prosthetic group. Given the known alterations in heme metabolism and redox metal distribution and the up regulation of heme oxygenase enzyme in Alzheimer’s disease (AD), we hypothesized that heme dyshomeostasis plays a key role in the pathogenesis. To begin testing this hypothesis, we used qRT-PCR to quantify the expression of aminolevulinate synthase (ALAS1) and porphobilinogen deaminase (PBGD), rate-limiting enzymes in the heme biosynthesis pathway. The relative expression of ALAS1 mRNA, the first and rate-limiting enzyme for heme biosynthesis under normal physiological conditions, was significantly (p < 0.05) reduced by nearly 90% in AD compared to control. Coordinately, the relative expression of PBGD mRNA, which encodes porphobilinogen deaminase, the third enzyme in the heme synthesis pathway and a secondary rate-limiting enzyme in heme biosynthesis, was also significantly (p < 0.02) reduced by nearly 60% in AD brain compared to control and significantly related to apolipoprotein E genotype (p < 0.005). In contrast, the relative expression of ALAD mRNA, which encodes aminolevulinate dehydratase, the second and a non-rate-limiting enzyme for heme biosynthesis, was unchanged between the two groups. Taken together, our results suggest regulation of cerebral heme biosynthesis is profoundly altered in AD and may contribute toward disease pathogenesis by affecting cell metabolism as well as iron homeostasis.

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Section: Discussionmentioning

confidence: 99%

Down-regulation of aminolevulinate synthase, the rate-limiting enzyme for heme biosynthesis in Alzheimer's disease

Dwyer

Smith

Richardson

et al. 2009

Neuroscience Letters

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“…Our present independent methods of immunolabelling and GFPtagging reveal dual localisations of PBGD in B16 melanoma cells, one cytosolic and the other nuclear. Recently, we have shown interaction between PBGD and a nuclear protein Ran-binding protein (Greenbaum et al, 2003). These findings are indicative of a possible dual function of PBGD, one enzymatic in the cytoplasmic heme pathway and an unknown role in the nucleus.…”

Section: Discussionmentioning

confidence: 73%

Differentiation-dependent photodynamic therapy regulated by porphobilinogen deaminase in B16 melanoma

et al. 2004

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Protoporphyrin IX (PpIX) synthesis by malignant cells is clinically exploited for photodiagnosis and photodynamic therapy following administration of 5-aminolevulinic acid (ALA). The expression and activity of the housekeeping porphobilinogen deaminase (PBGD) was correlated to PpIX synthesis in differentiating B16 melanoma cells. Differentiation was stimulated by two inducers, butyrate and hexamethylene bisacetamide (HMBA), both of which promote the formation of typical melanosomes and melanin, as well as morphological changeover. A marked decrease in total PBGD activity and PpIX synthesis was observed following stimulation by butyrate, while HMBA induced an opposite effect. In contrast, ferrochelatase levels remained unchanged. Photodynamic inactivation of the cells undergoing differentiation was largely dependent on the PpIX accumulation, which was modulated by the two inducers butyrate and HMBA. Fluorescence immunostaining with anti-PBGD antibodies revealed a major PBGD fraction in the nucleus and a minor fraction in the cytosol. This nuclear localisation pattern was confirmed by expression of PBGD fused to green fluorescence protein. We suggest that efficient photodynamic therapy of cancer facilitated by ALA administration can be enhanced using combined therapeutic modalities.

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“…PBG-D is a key enzyme in heme biosyntesis and it is expressed as two isoforms, a housekeeping isoform present in all cell types and a second isoform expressed only in erythroid cells (37). Greenbaum et al (38) showed that overexpression of the human housekeeping PGB-D has been found to induce C6 glioma cell differentiation toward astrocytes. Ickowicz Schwartz et al (22) demonstrated that stimulation with HMBA induced melanocytic differentiation accompained by a prominent increase in total PBGD as well as an increase of PpIX.…”

Section: Discussionmentioning

confidence: 99%

Chrysin-induced apoptosis is mediated through p38 and Bax activation in B16-F1 and A375 melanoma cells

Canini

2011

Int J Oncol

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Abstract. Chrysin (5,7-dihydroxyflavone) is a natural and biologically active compound extracted from honey, plants and propolis. It possesses anti-inflammatory activity, antioxidant properties and promotes cell death by perturbing cell cycle progression. In this study, our attention focused on the possible role that chrysin may have as a potential anti-cancer agent, and we tested its biological activity in murine and human melanoma cell lines (B16-F1 and A375). This study demonstrated that chrysin reduced melanoma cell proliferation and induced cell differentiation in both human and murine melanoma cells through synthesis increase and intracellular accumulation of protoporphirin IX (PpIX). Furthermore, following treatments with chrysin an increase in the expression of porphobilinogen deaminase (PBG-D) was noted. This study demontrated also that chrysin induces cell death in human and murine melanoma cells through caspase-dependent mechanisms, involving down-regulation of ERK 1/2, and activation of p38 MAP kinases. Induction of cell death may be a promising therapeutic approach in cancer therapy. Our results suggest that chrysin may be considered a potential candidate for both cancer prevention and treatment.

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

Cited by 28 publications

References 45 publications

Down-regulation of aminolevulinate synthase, the rate-limiting enzyme for heme biosynthesis in Alzheimer's disease

Down-regulation of aminolevulinate synthase, the rate-limiting enzyme for heme biosynthesis in Alzheimer's disease

Differentiation-dependent photodynamic therapy regulated by porphobilinogen deaminase in B16 melanoma

Chrysin-induced apoptosis is mediated through p38 and Bax activation in B16-F1 and A375 melanoma cells

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