Ran-GTPase与细胞周期调控：RCC1的作用与机制

需积分: 10 36 浏览量更新于2024-08-07 收藏 201KB PDF 举报

"这篇文章主要探讨了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的角色，以及它如何协调有丝分裂与S期的完成。Ran-GTPase系统在DNA复制、细胞周期进程和染色体分离等方面也起着关键作用。此外，Ran-GTPase在核质运输中的功能被广泛认识，通过其效应子进口素和出口素调节物质在细胞核与细胞质之间的转运。在有丝分裂期间，Ran-GTPase还影响微管聚合，可能对染色体附近的微管有特异性作用，并且对于核膜的再生至关重要。" 在细胞生物学中，Ran-GTPase是一个至关重要的分子开关，参与调控多种细胞活动。文章作者Jonathan D. Moore重点讨论了Ran-GTPase系统在细胞周期控制中的作用，特别是RCC1（染色体结合的鸟嘌呤核苷酸交换因子）的功能。RCC1被发现与Ran蛋白一起纯化，是Ran的小GTP酶的GEF，它促进Ran从GDP到GTP的转换，这个过程对于细胞周期的正常进行至关重要。 RCC1的主要职责是确保有丝分裂与S期的顺利协调。在S期，细胞进行DNA复制，而有丝分裂则是细胞分裂前的准备阶段。如果RCC1或Ran-GTPase网络发生缺陷，可能导致DNA复制出现问题，或者细胞无法正确退出有丝分裂，这可能导致染色体不准确的分配，从而引发遗传不稳定性和可能的肿瘤形成。 Ran-GTPase系统不仅在细胞周期中发挥作用，还在核质运输中扮演核心角色。Ran-GTP作为一种定位标志，指示核在细胞质中的位置。其效应子包括进口素和出口素，这些蛋白质在Ran-GTP的调控下改变它们的货物结合能力，以确保物质能朝正确的方向移动，即把核内物质运入细胞质，或将细胞质中的物质送入细胞核。在有丝分裂期间，Ran-GTPase的另一个重要功能是影响微管的聚合，这可能特别涉及到靠近染色体的区域。微管在细胞分裂过程中起到牵引染色体的作用，确保它们准确地分配到新的细胞中。最近的研究进一步揭示，Ran-GTPase对于核膜的再生具有决定性作用，这是细胞周期中的一个后期过程，核膜需要在有丝分裂后重新组装。 Ran-GTPase及其调节因子RCC1是细胞周期和细胞结构动态的关键调控者，它们的精确功能对维持细胞的正常生理状态和遗传稳定性至关重要。对这一系统的深入理解有助于揭示细胞分裂过程中的基本机制，也为治疗与细胞周期紊乱相关的疾病提供了潜在的靶点。

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

下载后可阅读完整内容，剩余8页未读，立即下载

weixin_38506798

粉丝: 4
资源: 937

Ran-GTPase与细胞周期调控：RCC1的作用与机制

拟南芥ROP蛋白结合活性因子（ICR1）基因的克隆及表达分析

Ran-GTPase 和细胞周期控制

Ran-GTPase：细胞周期控制的关键分子

Ran-GTPase在细胞周期调控中的作用

Ran-GTPase：连接细胞周期与核质运输的关键分子

Ran-GTPase和RCC1如何协调细胞周期过程，特别是在DNA复制、核质运输和微管聚合中起什么作用？

请解释Ran-GTPase和RCC1在细胞周期调控中的作用，以及它们如何影响DNA复制、核质运输和微管聚合。

Ran-GTPase和RCC1在细胞周期调控中扮演着哪些关键角色？它们是如何影响DNA复制、核质运输和微管聚合的？

GTPase-张力-分叉：GTPase-张力模型的分叉分析代码

TH upstream-inhibited CYFIP2 subnetwork for learning via cytoplasm to nucleus small GTPase mediated signal transduction

最新资源