Ran-GTPase：细胞周期控制的关键分子

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"这篇文章探讨了Ran-GTPase在细胞周期控制中的作用，特别是RCC1作为Ran-GTPase的鸟嘌呤核苷酸交换因子（GEF）如何协调有丝分裂与S期的完成。Ran-GTPase网络的缺陷会干扰细胞周期过程，如DNA复制、有丝分裂的退出以及在酵母中的染色体分离。它在核质运输中的关键角色也被广泛认识，通过Ran-GTP作为细胞周期中核定位的信号。Ran的效应因子，包括进口素和出口素，协助货物在核膜之间的运输。Ran-GTP调控这些因子的货物结合特性，确保货物向正确方向移动。此外，Ran-GTP还在有丝分裂期间影响微管聚合，可能特异性地影响着染色体附近的微管。最近的研究还发现Ran对于核被膜再生至关重要。" 这篇文章的核心知识点如下： 1. **Ran-GTPase系统**：Ran-GTPase是一种小GTP酶，参与多种细胞过程，尤其是细胞周期控制和核质运输。 2. **RCC1的角色**：RCC1是Ran-GTPase的鸟嘌呤核苷酸交换因子，负责催化Ran的GDP到GTP的交换，激活Ran-GTPase。 3. **细胞周期协调**：RCC1的作用在于确保有丝分裂的开始与S期（DNA复制阶段）的完成同步，任何Ran-GTPase网络的缺陷都会干扰这一过程。 4. **细胞周期过程的影响**：Ran-GTPase的异常可能导致DNA复制问题、有丝分裂退出障碍以及在酵母中的染色体不准确分离。 5. **核质运输**：Ran-GTPase系统通过Ran-GTP作为信号，指导货物（如蛋白质和其他分子）在细胞核与细胞质之间的运输。进口素和出口素作为Ran的效应因子，帮助物质的转运。 6. **有丝分裂中的作用**：Ran-GTP还影响微管的聚合，可能对染色体附近区域的微管动态有直接影响，这对有丝分裂中染色体的排列和分离至关重要。 7. **核被膜再生**：最新的研究揭示Ran-GTPase在核被膜再生过程中具有决定性作用，这对于细胞周期的正常进行和细胞分裂后的恢复至关重要。这些知识点展示了Ran-GTPase作为细胞内信号传递的关键分子，在细胞生命周期中扮演的重要角色，以及其功能的多样性和复杂性。

The Ran-GTPase and

cell-cycle control

Jonathan D. Moore

Summary

RCC1, the chromatin-bound guanine-nucleotide ex-

change factor (GEF) for the small nuclear GTPase, Ran,

is required for coordinating the onset of mitosis with

S-phase completion in mammalian cells. Other defects in

the Ran-GTPase network also result in disruption of cell-

cycle processes such as DNA replication, exit from

mitosis and, at least in budding yeast, accurate chromo-

some segregation. However, the Ran system is now best

known for its pivotal role in nucleocytoplasmic transport,

where RanGTP is used as a positional flag for the nucleus

during interphase. Ran's effectors are the shuttling

transport factors, importins and exportins, which facil-

itate the transit of cargoes between the nucleus and

cytoplasm: RanGTP regulates their cargo-binding prop-

erties so that they can move their cargo in the correct

direction. RanGTP also plays a separate role during

mitosis, influencing microtubule polymerisation, possi-

bly specifically in the vicinity of chromosomes. Most

recently, Ran has been shown to be crucial for

the regeneration of a nuclear envelope after exit from

mitosis. So, can the problems with cell-cycle progression

and control induced by perturbing the Ran-system be

attributed to defects in these three processes? This

article examines this issue, concentrating on vertebrate

systems. BioEssays 23:77±85, 2001.

ß 2001 John Wiley & Sons, Inc.

Introduction

In the late 1970s, Basilico and co-workers, inspired by the

discovery of the cell division cycle mutants in yeast, employed

a genetic approach to study the mammalian cell cycle and

isolated several cell lines with conditional mutations prevent-

ing entry into S-phase at high temperature. One of these lines,

tsBN2, had an interesting additional defect: if tsBN2 cells were

arrested in S-phase with hydroxyurea, then switched to the

restrictive temperature, most attempted a precocious mitosis

with incompletely replicated DNA.

(1)

A gene, designated

RCC1, was able to complement both the G

/S transition and

S/M checkpoint phenotypes.

(2)

The RCC1 protein proved to be

chromosome associated

(3)

and to be degraded at the

restrictive temperature.

(4)

How does RCC1 work? RCC1 was found to copurify with

Ran, a 25 kDa protein previously identified in a search for

Ras-related proteins.

(5,6)

RCC1 proved to be a guanine-

nucleotide exchange factor (GEF) for the Ran-GTPase;

(7)

analogy with the Ras system, RCC1 would therefore

``activate'' Ran by promoting exchange of GDP for GTP, the

predominant guanine nucleotide in cells. The S/M coordination

phenotype of tsBN2 cells, chromatin-bound localisation of

RCC1 and discovery that RCC1 is a RanGEF suggested that

replicating DNA might use RCC1 and RanGTP to signal to the

central cell-cycle control machinery that initiation of mitosis

should be delayed.

(7,8)

A prediction of this model, that

overexpression of a Ran mutant unable to hydrolyse GTP

should arrest cells at the G2/M transition, was tested and found

to be accurate.

(8)

Though the fission yeast homologues of Ran and RCC1

were also identified as gene products involved in coordinating

S-phase and mitosis,

(9)

it already seemed that the functions of

RCC1 and Ran might be more widespread (reviewed in Ref.

10). In budding yeast, it had been found that an RCC1

homologue is involved in the signalling pathways regulating

mating and various aspects of RNA maturation and transport.

Moreover, the yeast homologue of the Ran-GTPase activating

protein is necessary for mRNA export from the nucleus.

Finally, in the cell-free system provided by Xenopus egg

extracts, RCC1 is required for nuclear assembly and DNA

replication. The Ran-GTPase network thus appeared particu-

larly pleiotropic, impinging on a wide variety of cellular

processes. Figure 1 illustrates the range of cell-cycle transi-

tions that are sensitive to defects in the Ran-GTPase network

in different systems.

An indication of why this might be the case came from an

unexpected source. Nuclear protein import processes had

been reconstituted in a cell-free system using digitonin-

permeablised cells, providing an assay permitting the identi-

fication of the soluble factors that are essential for nucleocy-

toplasmic transport.

(11)

The first such factor purified was the

Ran-GTPase.

(12)

In eukaryotic cells, the separation of the sites

of transcription and translation dictates that all mRNA and

tRNA molecules must be exported to the cytoplasm, whereas

any protein required in the nucleus must be imported. Thus

defects in nucleocytoplasmic transport could potentially affect

the operation of many other cellular functions and regulatory

pathways. So are problems with nucleocytoplasmic transport

at the root of all the diverse phenotypes observed when the

BioEssays 23:77±85, ß 2001 John Wiley & Sons, Inc. BioEssays 23.1 77

Imperial Cancer Research Fund, Clare Hall Laboratories,

South Mimms, Herts, EN6 3LD, United Kingdom.

E-mail: Jonathan.Moore@icrf.icnet.uk

Funding agency: ICRF.

Problems and paradigms

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