Role of Schlafen 2 (SLFN2) in the Generation of Interferon α-induced Growth Inhibitory Responses

Efstratios Katsoulidis,Nathalie Carayol,Jennifer Woodard,Iwona Konieczna,Beata Majchrzak-Kita,Alison Jordan,Antonella Sassano,Elizabeth A Eklund,Eleanor N Fish,Leonidas C Platanias

doi:10.1074/jbc.m109.030445

Efstratios Katsoulidis, Nathalie Carayol + Show 8 more

Open Access

https://doi.org/10.1074/jbc.m109.030445

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Abstract

The precise STAT-regulated gene targets that inhibit cell growth and generate the antitumor effects of Type I interferons (IFNs) remain unknown. We provide evidence that Type I IFNs regulate expression of Schlafens (SLFNs), a group of genes involved in the control of cell cycle progression and growth inhibitory responses. Using cells with targeted disruption of different STAT proteins and/or the p38 MAP kinase, we demonstrate that the IFN-dependent expression of distinct Schlafen genes is differentially regulated by STAT complexes and the p38 MAP kinase pathway. We also provide evidence for a key functional role of a member of the SLFN family, SLFN2, in the induction of the growth-suppressive effects of IFNs. This is shown in studies demonstrating that knockdown of SLFN2 enhances hematopoietic progenitor colony formation and reverses the growth-suppressive effects of IFNalpha on normal hematopoietic progenitors. Importantly, NIH3T3 or L929 cells with stable knockdown of SLFN2 form more colonies in soft agar, implicating this protein in the regulation of anchorage-independent growth. Altogether, our data implicate SLFN2 as a negative regulator of the metastatic and growth potential of malignant cells and strongly suggest a role for the SLFN family of proteins in the generation of the antiproliferative effects of Type I IFNs.

Highlights

Type I interferons (IFNs)2 are potent inhibitors of cell growth of both normal and malignant cells in vitro and in vivo and play critical roles in the immune surveillance against cancer [1,2,3,4]
NIH3T3 cells were treated with mouse IFN␣ for different times, and the induction of mRNA expression for key members of the SLFN gene family was determined
The most pronounced induction was for SLFN1 (Fig. 1A), followed by SLFN5, SLFN2, and SLFN8 (Fig. 1, B, D, and E)

Summary

Introduction

Type I interferons (IFNs) are potent inhibitors of cell growth of both normal and malignant cells in vitro and in vivo and play critical roles in the immune surveillance against cancer [1,2,3,4]. The Jak-STAT pathway is the most important pathway in the regulation of IFN-inducible gene transcription and probably the best studied and characterized IFN␣-regulated signaling pathway to date An emerging model for the production of Type I IFN-inducible gene products involves transcriptional regulation of ISGs by Jak-STAT pathways, immediately followed by mRNA translation of such transcripts in an mTOR/ 4EBP1-dependent manner [17, 18]. The key IFN-inducible gene products that mediate growth inhibitory responses in different cell types remain largely unknown. The Schlafen (SLFN) (from the German word schlafen or sleeping) family of proteins includes several members that have previously been shown to control cell cycle progression and growth arrest (20 –26). Regardless, very little is known on the potential involvement of SLFN genes and their products in the induction

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