The centrosome protein NEDD1 as a potential pharmacological target to induce cell cycle arrest

Vanessa Tillement,Andreas Merdes,Chantal Etievant,Nicolas Roullet,Laurence Haren

doi:10.1186/1476-4598-8-10

Vanessa Tillement, Andreas Merdes + Show 3 more

Open Access

https://doi.org/10.1186/1476-4598-8-10

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Abstract

BackgroundNEDD1 is a protein that binds to the gamma-tubulin ring complex, a multiprotein complex at the centrosome and at the mitotic spindle that mediates the nucleation of microtubules.ResultsWe show that NEDD1 is expressed at comparable levels in a variety of tumor-derived cell lines and untransformed cells. We demonstrate that silencing of NEDD1 expression by treatment with siRNA has differential effects on cells, depending on their status of p53 expression: p53-positive cells arrest in G1, whereas p53-negative cells arrest in mitosis with predominantly aberrant monopolar spindles. However, both p53-positive and -negative cells arrest in mitosis if treated with low doses of siRNA against NEDD1 combined with low doses of the inhibitor BI2536 against the mitotic kinase Plk1. Simultaneous reduction of NEDD1 levels and inhibition of Plk1 act in a synergistic manner, by potentiating the anti-mitotic activity of each treatment.ConclusionWe propose that NEDD1 may be a promising target for controlling cell proliferation, in particular if targeted in combination with Plk1 inhibitors.

Highlights

neural precursor cell expressed (NEDD1) is a protein that binds to the gamma-tubulin ring complex, a multiprotein complex at the centrosome and at the mitotic spindle that mediates the nucleation of microtubules
To determine whether NEDD1 constitutes a potential target for future anti-cancer therapy, we investigate here the consequences of NEDD1-depletion by RNA silencing in a variety of cancer cell lines, and we analyse the effects of depletion on the cell cycle and on potential sensitisation to anti-mitotic agents
We examined the consequences of NEDD1-depletion on the cell cycle by flow cytometry

Summary

Introduction

NEDD1 is a protein that binds to the gamma-tubulin ring complex, a multiprotein complex at the centrosome and at the mitotic spindle that mediates the nucleation of microtubules. Considerable interest has focused on the role of the centrosome in cancer, because frequent abnormalities are found in tumor cells, such as supernumerary centrosomes or increased expression of centrosome proteins [1,2]. This phenomenon is termed "centrosome amplification", and has often been correlated with aggressive tumor growth. It has not been formally demonstrated that centrosome amplification can cause cancer, centrosome abnormalities can generate defective mitotic spindles and lead to mis-segregation of chromosomes and to aneuploidy [1,3]. In most cases spindle defects arrest the cell cycle in mitosis by activating the spindle assembly checkpoint, and lead to cell death

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