Expression of Prenylated Rab Acceptor 1 Domain Family, Member 2 (PRAF2) in Neuroblastoma: Correlation with Clinical Features, Cellular Localization, and Cerulenin-Mediated Apoptosis Regulation

Geerts, Dirk; Wallick, Christopher J.; Koomoa, Dana Lynn T.; Koster, Jan; Versteeg, Rogier; Go, Ramon; Bachmann, André S.

doi:10.1158/1078-0432.ccr-07-0829

Cited by 24 publications

(31 citation statements)

References 24 publications

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“…For these 88 tumors, extensive genetic and clinical descriptions were available from the patient files at the Academic Medical Center – University of Amsterdam, the Netherlands. Genome-wide Affymetrix U133Plus2.0 mRNA profiles were generated for these tumors, allowing insight into the clinical significance of interesting genes 8; 51; 52; 53; 54 .…”

Section: Resultsmentioning

confidence: 99%

Novel Interaction of Ornithine Decarboxylase with Sepiapterin Reductase Regulates Neuroblastoma Cell Proliferation

Lange

Geerts

Feith

et al. 2014

Journal of Molecular Biology

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Ornithine decarboxylase (ODC) is the sentinel enzyme in polyamine biosynthesis. Both ODC and polyamines regulate cell division, proliferation, and apoptosis. Sepiapterin reductase (SPR) catalyzes the last step in the biosynthesis of tetrahydrobiopterin (BH4), an essential cofactor of nitric oxide synthase (NOS), and has been implicated in neurological diseases but not yet in cancer. In this study, we present compelling evidence that native ODC and SPR physically interact, and we defined the individual amino acid residues involved in both enzymes using in silico protein-protein docking simulations. The resulting heterocomplex is a surprisingly compact structure, featuring two energetically and structurally equivalent binding modes both in monomer and dimer conformations. The novel interaction between ODC and SPR proteins was confirmed under physiological conditions by co-immunoprecipitation and co-localization in neuroblastoma (NB) cells. Importantly, we showed that siRNA-mediated knock-down of SPR expression significantly reduced endogenous ODC enzyme activity in NB cells, thus demonstrating the biological relevance of the ODC-SPR interaction. Finally, in a cohort of 88 human NB tumors we found that high SPR mRNA expression correlated significantly with poor survival prognosis using a Kaplan-Meier analysis (Logrank test P = 5 • 10−4), suggesting an oncogenic role for SPR in NB tumorigenesis. In conclusion, we showed that ODC binds SPR and thus propose a new concept in which two well-characterized biochemical pathways converge via the interaction of two enzymes. We identified SPR as a novel regulator of ODC enzyme activity, and based on clinical evidence present a model in which SPR drives ODC-mediated malignant progression in NB.

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Section: Resultsmentioning

confidence: 99%

Novel Interaction of Ornithine Decarboxylase with Sepiapterin Reductase Regulates Neuroblastoma Cell Proliferation

Lange

Geerts

Feith

et al. 2014

Journal of Molecular Biology

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“…4 d ). Since low‐stage tumors are associated with increased patient survival, the two‐year disease‐free survival rate of patients at INSS Stage 1 or 2 of the disease is 80–90%, whereas for Stage 3 and 4 patients it is only 40–60%,2, 44–46 we investigated PEA15 expression in correlation to INSS stage. Indeed, PEA15 expression was significantly higher in the INSS Stage 1 and 2 low‐stage tumors, when compared with high‐stage, often metastasized, tumors of Stage 4 ( p = 5.9 × 10 −4 and 9.0 × 10 −3 , respectively).…”

Section: Resultsmentioning

confidence: 99%

PEA15 impairs cell migration and correlates with clinical features predicting good prognosis in neuroblastoma

Gawecka

Geerts

Koster

et al. 2012

Intl Journal of Cancer

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ERK and RSK2 drive proliferation and invasion of many cancers. Phosphoprotein Enriched in Astrocytes 15 (PEA15) binds ERK and RSK2 and high PEA15 levels can impair ERK- and RSK2-dependent transcription. PEA15 expression also inversely correlates with cell motility and invasiveness. We therefore tested PEA15 effects on neuroblastoma cells in vitro. We further analyzed PEA15 expression in the context of clinical and genetic features of neuroblastoma in tumor samples to determine its correlation with disease progression. Affymetrix microarray analysis was performed using 24 different neuroblastoma cell lines. Cell lines expressing low to intermediate levels of PEA15 were chosen for in vitro functional studies. The cell line results were verified by Affymetrix analysis of 3 different neuroblastic tumor types (total of 110 samples) PEA15 overexpression inhibited neuroblastoma migration in vitro. We verified that inhibition of motility required PEA15 interaction with its binding partners ERK and RSK2. Additionally, synthetic inhibitors of RSK2 suppressed integrin-dependent migration. PEA15 expression correlates with clinical parameters and a 25% increase in patient survival rate. The highest PEA15 levels were found in low stage, more differentiated and less metastatic neuroblastic tumors, and correlated with lack of MYCN amplification. PEA15 blocks neuroblastoma migration through inhibition of ERK/RSK2 signaling. PEA15 expression levels correlate with favorable clinical features suggesting that PEA15 limits metastatic progression of neuroblastoma. Thus, PEA15 and its partners ERK and RSK2 are potential targets for the development of new therapeutics to impede progression of minimal residual disease in patients with high-risk neuroblastoma.

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“…In human, yeast, and mouse, PRA1 resides predominantly in the Golgi apparatus (Liang and Li, 2000;Huh et al, 2003;Sivars et al, 2003). However, PRA1 proteins have been reported in different trafficking compartments, such as the ER (Abdul-Ghani et al, 2001;Schweneker et al, 2005;Liu et al, 2006), synaptic vesicles (Fenster et al, 2000), COPI and COPII vesicles (Otte et al, 2001;Gilchrist et al, 2006), and endosomes (Schweneker et al, 2005;Geerts et al, 2007). To determine the subcellular localization of the 19 AtPRA1 proteins, their full-length open reading frames were fused to the enhanced GFP reporter protein (EGFP) and stably produced in Arabidopsis seedlings.…”

Section: Subcellular Localization Of the Atpra1 Proteins In Arabidopsismentioning

confidence: 99%

ThePRA1Gene Family in Arabidopsis

Kamei

Boruc²,

Vandepoele³

et al. 2008

Plant Physiology

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Prenylated Rab acceptor 1 (PRA1) domain proteins are small transmembrane proteins that regulate vesicle trafficking as receptors of Rab GTPases and the vacuolar soluble N-ethylmaleimide-sensitive factor attachment receptor protein VAMP2. However, little is known about PRA1 family members in plants. Sequence analysis revealed that higher plants, compared with animals and primitive plants, possess an expanded family of PRA1 domain-containing proteins. The Arabidopsis (Arabidopsis thaliana) PRA1 (AtPRA1) proteins were found to homodimerize and heterodimerize in a manner corresponding to their phylogenetic distribution. Different AtPRA1 family members displayed distinct expression patterns, with a preference for vascular cells and expanding or developing tissues. AtPRA1 genes were significantly coexpressed with Rab GTPases and genes encoding vesicle transport proteins, suggesting an involvement in the vesicle trafficking process similar to that of their animal counterparts. Correspondingly, AtPRA1 proteins were localized in the endoplasmic reticulum, Golgi apparatus, and endosomes/ prevacuolar compartments, hinting at a function in both secretory and endocytic intracellular trafficking pathways. Taken together, our data reveal a high functional diversity of AtPRA1 proteins, probably dealing with the various demands of the complex trafficking system.

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Expression of Prenylated Rab Acceptor 1 Domain Family, Member 2 (PRAF2) in Neuroblastoma: Correlation with Clinical Features, Cellular Localization, and Cerulenin-Mediated Apoptosis Regulation

Cited by 24 publications

References 24 publications

Novel Interaction of Ornithine Decarboxylase with Sepiapterin Reductase Regulates Neuroblastoma Cell Proliferation

Novel Interaction of Ornithine Decarboxylase with Sepiapterin Reductase Regulates Neuroblastoma Cell Proliferation

PEA15 impairs cell migration and correlates with clinical features predicting good prognosis in neuroblastoma

ThePRA1Gene Family in Arabidopsis

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