STAT蛋白激活与细胞生长调控机制详析

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"STAT蛋白的激活与生长调控是细胞生物学领域的重要研究课题，特别是在信号转导和基因转录层面。本文由Jacqueline F. Bromberg撰写，主要聚焦于信号转导和转录激活因子（Signal Transducers and Activators of Transcription, STAT）的作用机制及其在细胞生长控制中的关键角色。STAT家族是一类跨膜蛋白质，它们作为细胞外信号向核内传递的桥梁，参与到细胞命运决定的过程中。首先，作者详细阐述了STAT蛋白的基本结构，包括其由胞外结构域、跨膜区和胞内功能域组成，这些结构域协同工作，使得STAT能够在接收到相应配体（如干扰素）的信号后发生磷酸化，从而转变为活性形式。这个磷酸化过程至关重要，因为它激活了STAT蛋白的DNA结合能力，使其能够结合到特定的基因启动子区域，进而调控基因表达。接着，文章探讨了调节STAT活性的关键分子，这些分子可能包括激酶、磷脂酶C和抑制性蛋白质等，它们在STAT的磷酸化和去磷酸化过程中发挥调控作用，决定了信号转导的精确时序和强度。此外，作者还提到了STAT蛋白缺失的不同突变型小鼠模型，这些模型揭示了各个STAT成员对细胞生长、分化、凋亡以及恶性转化的影响，为理解正常生理和病理状态下的细胞行为提供了重要线索。最后，作者指出失调的STAT信号通路在癌症的发生发展中起着关键作用。例如，某些癌症中，STAT信号异常激活可能导致细胞增殖失控、抗凋亡基因过度表达，以及抑癌基因沉默，从而促进肿瘤形成和发展。论文通过举例说明了这些病理机制，并强调了在抗癌策略中靶向STAT信号通路的重要性。这篇文章深入剖析了STAT蛋白在细胞生长调控中的核心作用，展示了其在生物学和医学研究中的关键地位，为进一步理解信号转导网络在健康和疾病中的动态平衡提供了深入洞察。"

Activation of STAT proteins and

growth control

Jacqueline F. Bromberg

Summary

This review will discuss how STAT (

Signal Transducers

and

Activators of Transcription) proteins, a group of

transcription factors that transmit signals from the

extracellular surface of cells to the nucleus, are involved

in growth control. I will discuss the anatomy of a STAT

protein, how it works as a transcription factor, the mole-

cules that regulate its ``activity'', the phenotypes of mice

that lack individual STAT proteins and their involvement

in growth, differentiation, apoptosis, and transformation.

Finally, a number of examples will be presented of how

dysregulated STAT signaling may be involved in the

pathogenesis of cancer. BioEssays 23:161±169, 2001.

ß 2001 John Wiley & Sons, Inc.

Introduction

Over ten years ago, during work on how interferons (IFNs)

mediate activation of genes, STAT proteins were discovered,

specifically STAT1 and STAT2.

(1)

Since that time seven mam-

malian STATs and an increasing number of non-mammalian

STATs, have been isolated and shown to play important roles

in growth and development. STAT proteins are a family of

latent transcription factors that are abundantly produced in

many cell types. They become activated by phosphorylation

on a single tyrosine (at the carboxyl end of the molecule),

typically in response to extracellular ligands. An active STAT

dimer is formed through reciprocal interactions between the

SH2 domain of one monomer and the phosphorylated tyrosine

of the other.

(2)

The dimers accumulate in the nucleus,

recognize specific DNA elements in the promoters of genes

and activate transcription. Growth control and survival of

normal cells in a developing or an adult mammal are carefully

balanced. Many of the signals that influence this balance are

delivered by circulating polypeptides, whose binding to cell

surface receptors governs gene-specific transcription. Over

forty different polypeptides can mediate STAT activation

through either cytokine or G-protein receptors with associated

JAK kinases or growth factors (e.g. EGF, PDGF, CSF-1)

acting through intrinsic receptor tyrosine kinases.

(3)

In addi-

tion, numerous non-receptor tyrosine kinases (for example src

and abl) lead to STAT activation. It has been shown that

human cancer cells have often lost normal control of these

signaling systems. In addition to persistent unregulated

mitogenic signaling, the lack of suppressive signals (tumor

suppressors) is also critical in the development of cancers. In

this article, I will describe the molecular anatomy of the STAT

proteins, how they behave as transcription factors, the

mechanisms by which STAT proteins become activated and

regulated, the importance of STAT signaling in normal growth

and development and finally the role of dysregulated STAT

signaling in the pathogenesis of cancer.

STAT domains

STAT proteins were originally discovered as DNA-binding

proteins that mediate IFN signaling. We now know, however,

that they also play a central role in cytokine, growth factor, G-

protein and oncogenic tyrosine kinase signaling. Altogether,

there are seven known mammalian STAT family members.

Each is initially latent in the cytoplasm of cells (however not

necessarily as a monomer), becomes activated by phospho-

rylation on a single tyrosine residue (  700), and dimerizes by

virtue of a reciprocal ÿ SH2 phospho-tyrosine interaction.

(1)

The dimeric STAT protein accumulates in the nucleus, binds

DNA and drives transcription. (Fig. 1). STAT proteins in the

nucleus are subsequently inactivated by tyrosine dephos-

phorylation and then return to the cytoplasm.

(4)

Determination of the three-dimensional structures of the

core of STAT1 and STAT3 (from residues  130±712; lacking

an N-terminal and C-terminal domain) bound to DNA revealed

four domains (Fig. 2).

(2)

From residues  130±320, there are

four long helical coils, which interact with each other and

provide large surfaces to interact with other proteins; residues

 320±490 constitute the DNA-binding domain, a region of

BioEssays 23:161±169, ß 2001 John Wiley & Sons, Inc. BioEssays 23.2 161

Department of Medicine, Memorial Sloan-Kettering Cancer Center,

1275 York Avenue, NY 10021. E-mail: bromberj@mskcc.org

Funding agencies: McDonnell Foundation Award.

Abbreviations: CDK, Cyclin Dependent Kinase; CIS1, Cytokine

Inducible Src homology 2-domain containing protein; CSF-1, Colony

Stimulating Factor; EGF, Epidermal Growth Factor; EPO, Erythro-

poietin; FGF, Fibroblast Growth Factor; GCMSF, Granulocyte Colony

Macrophage Stimulating Factor; GR, Glucocorticoid Receptor; IFN,

Interferon; IL, Interleukin; JAB, JAK-Binding protein; JAK, Janus

Kinase; MCM, Mini-Chromosome Maintenance; MIP-1, Macrophage

Inflammatory Protein; PDGF, Platelet-Derived Growth Factor; PIAS,

Protein Inhibitors of Activated STATs; PRL, Prolactin; SH2, Src

Homology Domain; SHP, Src Homology Protein Tyrosine Phospha-

tase; SOCS, Suppressor of Cytokine Signaling; SSI, STAT-Induced

STAT-Inhibitor; STAT, Signal Transducers and Activators of Tran-

scription; TNF, Tumor Necrosis Factor.

Review articles

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