Dysregulation of Microtubule Nucleating Proteins in Cancer Cells.

Pavel Dráber,Eduarda Dráberová

doi:10.3390/cancers13225638

Abstract

Simple SummaryThe dysfunction of microtubule nucleation in cancer cells changes the overall cytoskeleton organization and cellular physiology. This review focuses on the dysregulation of the γ-tubulin ring complex (γ-TuRC) proteins that are essential for microtubule nucleation. Recent research on the high-resolution structure of γ-TuRC has brought new insight into the microtubule nucleation mechanism. We discuss the effect of γ-TuRC protein overexpression on cancer cell behavior and new drugs directed to γ-tubulin that may offer a viable alternative to microtubule-targeting agents currently used in cancer chemotherapy.In cells, microtubules typically nucleate from microtubule organizing centers, such as centrosomes. γ-Tubulin, which forms multiprotein complexes, is essential for nucleation. The γ-tubulin ring complex (γ-TuRC) is an efficient microtubule nucleator that requires additional centrosomal proteins for its activation and targeting. Evidence suggests that there is a dysfunction of centrosomal microtubule nucleation in cancer cells. Despite decades of molecular analysis of γ-TuRC and its interacting factors, the mechanisms of microtubule nucleation in normal and cancer cells remains obscure. Here, we review recent work on the high-resolution structure of γ-TuRC, which brings new insight into the mechanism of microtubule nucleation. We discuss the effects of γ-TuRC protein dysregulation on cancer cell behavior and new compounds targeting γ-tubulin. Drugs inhibiting γ-TuRC functions could represent an alternative to microtubule targeting agents in cancer chemotherapy.

Highlights

Microtubules are cytoskeletal polymers that are indispensable for vital cellular activities, such as cell division, migration, maintenance of cell shape, and ordered vesicle transport powered by motor proteins
An and patient survival and performance. These results suggested that the aberrant essential role in regulating microtubule nucleation in breast cancer is played by γ-tubulin expression of both γ-tubulin maytype be linked to malignantprotein)/BARD1 changes in glial ubiquitylation by βIII-tubulin the BRCA1and
More than 25 years of research on γ-tubulin complexes led to the conclusion that they are almost universally involved in microtubule nucleation

Summary

Introduction

Microtubules are cytoskeletal polymers that are indispensable for vital cellular activities, such as cell division, migration, maintenance of cell shape, and ordered vesicle transport powered by motor proteins. Centroous scaffold effector kinases,and andcoordination phosphatases involved in the pathways formation somes serve and as hubs for proteins, the integration ofare various signaling of PCM-ordered layers and the organization of microtubules [5,6]. These non-centrosomal sites play a Tubulin, together with other proteins, named γ-tubulin complex proteins (GCPs), assemsignificant role in the architecture of the microtubule network. Its structural aberrations represent a hallmark of human cancers with direct conseBy contrast, many cancer cells harbor extra centrosomes [14]. Numerous its structural aberrations represent a hallmark of human cancers with direct consequences studies have correlated the presence and the degree of centrosome amplification with infor chromosomal instability and can trigger cellular invasion [15,16]. Specific attention will be given to the high-resolution structure of γ-TuRC, dysregulation of γ-TuRC building proteins in cancer cells, and to new drugs targeting γ-tubulin functions

Microtubules as Targets in Cancer Chemotherapy

Dysregulation of γ-Tubulin in Cancer Cells

Dysregulation of the Other γ-TuRC Building Components

Therapeutic Potential of γ-Tubulin Targeting

Findings

Conclusions and Perspectives