Tài liệu Báo cáo khoa học: Regulation of DNA fragmentation: the role of caspases and phosphorylation

REVIEW ARTICLE

Regulation of DNA fragmentation: the role of caspases

and phosphorylation

Ikuko Kitazumi and Masayoshi Tsukahara

Bio Process Research and Development Laboratories, Kyowa Hakko Kirin Co. Ltd, Gunma, Japan

Introduction

Apoptosis is a crucial cellular mechanism that is

involved in inflammation, cell differentiation and cell

proliferation. As a form of cell death, it is character￾ized by distinctive morphological and biochemical

changes, including plasma membrane blebbing, phos￾phatidylserine exposure, nuclear condensation and

DNA fragmentation [1]. These cellular changes are

largely mediated by caspases, a family of cysteinyl

aspartate-specific proteases whose target proteins are

important indicators of apoptotic cell death [2].

Keywords

apoptosis; caspase; DNA fragmentation;

okadaic acid; phosphorylation

Correspondence

M. Tsukahara, Bio Process Research and

Development Laboratories, Kyowa Hakko

Kirin Co. Ltd, 100-1 Hagiwara, Takasaki,

Gunma 370-0013, Japan

Fax: 81 27 353 7400

Tel: 81 27 353 7382

E-mail: masayoshi.tsukahara@kyowa￾kirin.co.jp

(Received 10 September 2010, revised 18

November 2010, accepted 26 November

2010)

doi:10.1111/j.1742-4658.2010.07975.x

DNA fragmentation is a hallmark of apoptosis that is induced by apopto￾tic stimuli in various cell types. Apoptotic signal pathways, which eventu￾ally cause DNA fragmentation, are largely mediated by the family of

cysteinyl aspartate-specific protease caspases. Caspases mediate apoptotic

signal transduction by cleavage of apoptosis-implicated proteins and the

caspases themselves. In the process of caspase activation, reversible protein

phosphorylation plays an important role. The activation of various pro￾teins is regulated by phosphorylation and dephosphorylation, both

upstream and downstream of caspase activation. Many kinases⁄ phosphata￾ses are involved in the control of cell survival and death, including the

mitogen-activated protein kinase signal transduction pathways. Reversible

protein phosphorylation is involved in the widespread regulation of cellular

signal transduction and apoptotic processes. Therefore, phosphatase ⁄ kinase

inhibitors are commonly used as apoptosis inducers⁄ inhibitors. Whether

protein phosphorylation induces apoptosis depends on many factors, such

as the type of phosphorylated protein, the degree of activation and the

influence of other proteins. Phosphorylation signaling pathways are intri￾cately interrelated; it was previously shown that either induction or inhibi￾tion of phosphorylation causes cell death. Determination of the

relationship between protein and phosphorylation helps to reveal how

apoptosis is regulated. Here we discuss DNA fragmentation and protein

phosphorylation, focusing on caspase and serine ⁄threonine protein phos￾phatase activation.

Abbreviations

AIF, apoptosis-inducing factor; CA, calyculin A; CAD, caspase-activated DNase; DFF, DNA fragmentation factor; EndoG, endonuclease G;

ERK, extracellular signal-regulated kinase; HtrA2, high temperature requirement protein A2; ICAD, inhibitor of caspase-activated DNase;

JNK, Jun NH2 terminal kinase; MAPK, mitogen-activated protein kinase; OA, okadaic acid; PARP, poly(ADP-ribose) polymerase;

PP, serine ⁄ threonine protein phosphatase; ST, staurosporine; TM, tautomycin; XIAP, X-linked inhibitor of apoptosis.

FEBS Journal 278 (2011) 427–441 ª 2010 The Authors Journal compilation ª 2010 FEBS 427