The promyelocytic leukemia protein PML is organized into nuclear bodies which mediate suppression of oncogenic transformation and of growth. The biochemical functions of PML bodies are unknown, despite their involvement in several human disorders. We demonstrate that eukaryotic initiation factor 4E (eIF4E) directly binds the PML RING, a domain required for association with bodies and for suppression of transformation. Nuclear eIF4E functions in nucleocytoplasmic transport of a subset of transcripts including Cyclin D1. Present studies indicate that some PML requires the evolutionarily older eIF4E protein for association with nuclear bodies. Furthermore, PML RING modulates eIF4E activity by drastically reducing its af®nity for its substrate, 5¢ m 7 G cap of mRNA. We demonstrate that eIF4E requires cap binding for transport of Cyclin D1 mRNA and subsequent transformation activity. Additionally, PML reduces the af®nity of eIF4E for m 7 G mRNA cap, causing a reduction in Cyclin D1 protein levels and consequent transformation inhibition. PML is the ®rst factor shown to modulate nuclear eIF4E function. These ®ndings provide the ®rst biochemical framework for understanding the transformation suppression activity of PML. Keywords: eukaryotic initiation factor 4E/nuclear domain 10/promyelocytic leukemia/PML oncogenic domains/RING

Conducting research in conflict environments is a challenge, given their complexity and common attitudes of distrust and suspicion. Yet, conflict and methodology are usually analyzed as separate fields of interest. Methodological aspects of field work in conflict environments have not been systematically analyzed. This article addresses the central methodological problems of research conducted in conflict environments. We suggest the use of the snowball sampling method (hereafter, SSM) as an answer to these challenges. The effectiveness of this method has been recognized as significant in a variety of cases, mainly regarding marginalized populations. We claim that in conflict environments, the entire population is marginalized to some degree, making it ‘hidden’ from and ‘hard to reach’ for the outsider researcher. The marginalization explains why it is difficult to locate, access and enlist the cooperation of the research populations, which in a non-conflict context would not have been difficult to do. SSM directly addresses the fears and mistrust common to the conflict environment and increases the likelihood of trusting the researcher by introduction through a trusted social network. We demonstrate how careful use of SSM as a ‘second best’ but still valuable methodology can help generate cooperation. Therefore, the evaluation of SSM, its advantages and limitations in implementation in conflict environments can be an important contribution to the methodological training of researchers. In addition to its effectiveness under conditions of conflict, SSM may, in some cases, actually make the difference between research conducted under constrained conditions and research not conducted at all. Together with our experiences in the field, we supply several insights and recommendations for optimizing the use of SSM in a conflict environment.

The translation initiation factor eIF4E is involved in the modulation of cellular growth. In the nucleus, where eIF4E is associated with PML nuclear bodies, eIF4E mediates nucleocytoplasmic transport of speci®c transcripts, and this contributes to its transformation activity. Surprisingly, we found that a transcription factor, the proline-rich homeodomain protein PRH, is a negative regulator of eIF4E in myeloid cells, interacting with eIF4E through a conserved binding site typically found in translational regulators. Through this interaction, PRH inhibits eIF4E-dependent mRNA transport and subsequent transformation. These activities of PRH are independent of its transcriptional functions. Further, we found that 199 homeodomain proteins contain potential eIF4E-binding sites. Thus, there could be many tissue-speci®c regulators of eIF4E. These ®ndings provide a model for regulation of a general factor, eIF4E, in tissuespeci®c contexts, and suggest that its regulation is important in differentiation and development.