Tài liệu Báo cáo khoa học: Interferon-a induces sensitization of cells to inhibition of protein

Interferon-a induces sensitization of cells to inhibition of

protein synthesis by tumour necrosis factor-related

apoptosis-inducing ligand

Ian W. Jeffrey, Androulla Elia, Ste´phanie Bornes*, Vivienne J. Tilleray, Karthiga Gengatharan and

Michael J. Clemens

Translational Control Group, Centre for Molecular and Metabolic Signalling, Division of Basic Medical Sciences, St George’s, University of

London, UK

Members of the tumour necrosis factor-a (TNFa) fam￾ily are well known as inhibitors of cell growth and

inducers of apoptosis in a wide variety of systems [1].

We have previously shown that both TNFa and

tumour necrosis factor-related apoptosis-inducing

ligand (TRAIL) cause rapid downregulation of global

protein synthesis in MCF-7 breast cancer cells [2]. In

addition, studies with embryonic fibroblasts deficient

in the interferon (IFN)-inducible, double-stranded

RNA-dependent protein kinase (PKR) demonstrated

that expression of this protein is essential for the

TNFa-induced inhibition of translation [2]. Consistent

with these observations, the a subunit of polypeptide

chain eukaryotic initiation factor eIF2, which is a sub￾strate for PKR, becomes more highly phosphorylated

in cells exposed to TRAIL or TNFa. It is well estab￾lished that the phosphorylation of eIF2a by PKR

results in inhibition of polypeptide chain initiation [3].

There are, however, additional events that impinge

on the translational machinery in TNFa-treated or

TRAIL-treated cells. In particular, we have observed

increased association of the inhibitory protein eukary￾otic initiation factor 4E-binding protein (4E-BP1)

with the mRNA cap-binding factor eIF4E in cells

Keywords

caspases; interferon-a; polypeptide chain

initiation; protein synthesis; TRAIL

Correspondence

M. J. Clemens, Division of Basic Medical

Sciences, St George’s, University of

London, Cranmer Terrace, London SW17

0RE, UK

Fax: +44 20 8725 2992

Tel: +44 20 8725 5762

E-mail: [email protected]

*Present address

De´partement d’Oncoge´ne´tique, Centre

Biome´dicale de Recherche et Valorisation,

Clermont-Ferrand, France.

(Received 15 March 2006, revised 19 May

2006, accepted 12 June 2006)

doi:10.1111/j.1742-4658.2006.05374.x

Tumour cells are often sensitized by interferons to the effects of tumour

necrosis factor-a-related apoptosis-inducing ligand (TRAIL). We have

demonstrated previously that TRAIL has an inhibitory effect on protein

synthesis [Jeffrey IW, Bushell M, Tilleray VJ, Morley S & Clemens MJ

(2002) Cancer Res 62, 2272–2280] and we have therefore examined the

consequences of prior interferon-a treatment for the sensitivity of transla￾tion to inhibition by TRAIL. Interferon treatment alone has only a

minor effect on protein synthesis but it sensitizes both MCF-7 cells and

HeLa cells to the downregulation of translation by TRAIL. The inhibi￾tion of translation is characterized by increased phosphorylation of the a

subunit of eukaryotic initiation factor eIF2 and dephosphorylation of the

eIF4E-binding protein 4E-BP1. Both of these effects, as well as the

decrease in overall protein synthesis, require caspase-8 activity, although

they precede overt apoptosis by several hours. Interferon-a enhances the

level and ⁄ or the extent of activation of caspase-8 by TRAIL, thus provi￾ding a likely explanation for the sensitization of cells to the inhibition of

translation.

Abbreviations

4E-BP, eukaryotic initiation factor 4E binding protein; BID, Bcl-2-interacting death protein; eIF, eukaryotic initiation factor; FADD, Fas￾associated death domain; IFN, interferon; PARP, poly(ADP-ribose) polymerase; PKR, RNA-dependent protein kinase; TNFa, tumour necrosis

factor-a; TRAIL, tumour necrosis factor-a-related apoptosis-inducing ligand; zIETD.FMK, zIle-Glu-Thr-Asp-fluoromethyl ketone.

3698 FEBS Journal 273 (2006) 3698–3708 ª 2006 The Authors Journal compilation ª 2006 FEBS