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Neuroblastoma tumorigenesis is regulated through the Nm23-H1/h-Prune C-terminal interaction.

Carotenuto M, Pedone E, Diana D, de Antonellis P, Džeroski S, Marino N, Navas L, Di Dato V, Scoppettuolo MN, Cimmino F, Correale S, Pirone L, Monti SM, Bruder E, Zenko B, Slavkov I, Pastorino F, Ponzoni M, Schulte JH, Schramm A, Eggert A, Westermann F, Arrigoni G, Accordi B, Basso G, Saviano M, Fattorusso R, Zollo M - Sci Rep (2013)

Bottom Line: H-Prune is the most characterized Nm23-H1 binding partner, and its overexpression has been shown in different human cancers.We developed a competitive permeable peptide (CPP) to impair the formation of the Nm23-H1/h-Prune complex and demonstrated that CPP causes impairment of cell motility, substantial impairment of tumor growth and metastases formation.We also identified two other proteins (PTPRA and TRIM22) with expression levels significantly affected by CPP.

View Article: PubMed Central - PubMed

Affiliation: Centro di Ingegneria Genetica e Biotecnologie Avanzate-CEINGE, Naples, Italy.

ABSTRACT
Nm23-H1 is one of the most interesting candidate genes for a relevant role in Neuroblastoma pathogenesis. H-Prune is the most characterized Nm23-H1 binding partner, and its overexpression has been shown in different human cancers. Our study focuses on the role of the Nm23-H1/h-Prune protein complex in Neuroblastoma. Using NMR spectroscopy, we performed a conformational analysis of the h-Prune C-terminal to identify the amino acids involved in the interaction with Nm23-H1. We developed a competitive permeable peptide (CPP) to impair the formation of the Nm23-H1/h-Prune complex and demonstrated that CPP causes impairment of cell motility, substantial impairment of tumor growth and metastases formation. Meta-analysis performed on three Neuroblastoma cohorts showed Nm23-H1 as the gene highly associated to Neuroblastoma aggressiveness. We also identified two other proteins (PTPRA and TRIM22) with expression levels significantly affected by CPP. These data suggest a new avenue for potential clinical application of CPP in Neuroblastoma treatment.

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Related in: MedlinePlus

Three-dimensional model of full-length h-Prune.(a) The amino acids showing large variations upon complex formation with Nm23-H1 and the CPP peptide are mapped in cyan. The regions colored in magenta correspond to the amino acids recognized exclusively by Nm23-H1, as shown in detail in panels b and c.
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f3: Three-dimensional model of full-length h-Prune.(a) The amino acids showing large variations upon complex formation with Nm23-H1 and the CPP peptide are mapped in cyan. The regions colored in magenta correspond to the amino acids recognized exclusively by Nm23-H1, as shown in detail in panels b and c.

Mentions: A three-dimensional model of the full-length h-Prune protein was then built using an N-terminal (amino acids 1–352) h-Prune structure derived via homology modeling and attached to a representative NMR h-Prune C-terminal structure. The full-length h-Prune model was then refined through molecular dynamics simulation in vacuo. The analysis of the whole structure indicates that the N terminus (amino acids 353–370) of the h-Prune C-terminal (Fig. 3a–c) is indeed part of the h-Prune DHH2 domain, and in particular constitutes the second part of the last helix and a turned region that interacts with the preceding helix; accordingly, this region in the h-Prune C-terminal has a clear helical propensity (Fig. 2c). Therefore, the IDP h-Prune C-terminal domain that does not have specific interactions with the globular portions of the whole protein begins at residue 371 and retains the secondary structure propensities (α2 and α3) indicated by the NMR analysis, with a more compact C-terminal region (amino acids 410–440; see Movie 1).


Neuroblastoma tumorigenesis is regulated through the Nm23-H1/h-Prune C-terminal interaction.

Carotenuto M, Pedone E, Diana D, de Antonellis P, Džeroski S, Marino N, Navas L, Di Dato V, Scoppettuolo MN, Cimmino F, Correale S, Pirone L, Monti SM, Bruder E, Zenko B, Slavkov I, Pastorino F, Ponzoni M, Schulte JH, Schramm A, Eggert A, Westermann F, Arrigoni G, Accordi B, Basso G, Saviano M, Fattorusso R, Zollo M - Sci Rep (2013)

Three-dimensional model of full-length h-Prune.(a) The amino acids showing large variations upon complex formation with Nm23-H1 and the CPP peptide are mapped in cyan. The regions colored in magenta correspond to the amino acids recognized exclusively by Nm23-H1, as shown in detail in panels b and c.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3584926&req=5

f3: Three-dimensional model of full-length h-Prune.(a) The amino acids showing large variations upon complex formation with Nm23-H1 and the CPP peptide are mapped in cyan. The regions colored in magenta correspond to the amino acids recognized exclusively by Nm23-H1, as shown in detail in panels b and c.
Mentions: A three-dimensional model of the full-length h-Prune protein was then built using an N-terminal (amino acids 1–352) h-Prune structure derived via homology modeling and attached to a representative NMR h-Prune C-terminal structure. The full-length h-Prune model was then refined through molecular dynamics simulation in vacuo. The analysis of the whole structure indicates that the N terminus (amino acids 353–370) of the h-Prune C-terminal (Fig. 3a–c) is indeed part of the h-Prune DHH2 domain, and in particular constitutes the second part of the last helix and a turned region that interacts with the preceding helix; accordingly, this region in the h-Prune C-terminal has a clear helical propensity (Fig. 2c). Therefore, the IDP h-Prune C-terminal domain that does not have specific interactions with the globular portions of the whole protein begins at residue 371 and retains the secondary structure propensities (α2 and α3) indicated by the NMR analysis, with a more compact C-terminal region (amino acids 410–440; see Movie 1).

Bottom Line: H-Prune is the most characterized Nm23-H1 binding partner, and its overexpression has been shown in different human cancers.We developed a competitive permeable peptide (CPP) to impair the formation of the Nm23-H1/h-Prune complex and demonstrated that CPP causes impairment of cell motility, substantial impairment of tumor growth and metastases formation.We also identified two other proteins (PTPRA and TRIM22) with expression levels significantly affected by CPP.

View Article: PubMed Central - PubMed

Affiliation: Centro di Ingegneria Genetica e Biotecnologie Avanzate-CEINGE, Naples, Italy.

ABSTRACT
Nm23-H1 is one of the most interesting candidate genes for a relevant role in Neuroblastoma pathogenesis. H-Prune is the most characterized Nm23-H1 binding partner, and its overexpression has been shown in different human cancers. Our study focuses on the role of the Nm23-H1/h-Prune protein complex in Neuroblastoma. Using NMR spectroscopy, we performed a conformational analysis of the h-Prune C-terminal to identify the amino acids involved in the interaction with Nm23-H1. We developed a competitive permeable peptide (CPP) to impair the formation of the Nm23-H1/h-Prune complex and demonstrated that CPP causes impairment of cell motility, substantial impairment of tumor growth and metastases formation. Meta-analysis performed on three Neuroblastoma cohorts showed Nm23-H1 as the gene highly associated to Neuroblastoma aggressiveness. We also identified two other proteins (PTPRA and TRIM22) with expression levels significantly affected by CPP. These data suggest a new avenue for potential clinical application of CPP in Neuroblastoma treatment.

Show MeSH
Related in: MedlinePlus