Gamma interferon and cadmium treatments modulate eukaryotic initiation factor 4E-dependent mRNA transport of cyclin D1 in a PML-dependent manner

The eukaryotic initiation factor 4E (eIF4E), when dysregulated, transforms cells. A substantial fraction of eIF4E forms nuclear bodies that colocalize with those associated with the promyelocytic leukemia protein PML. Overexpression studies indicate that nuclear eIF4E promotes the transport of cyclin D1 mRNA from the nucleus to the cytoplasm and that PML is a key negative regulator of this function. Since previous studies used overexpression methods, the physiological relevance of eIF4E mRNA transport function or its interaction with PML remained unknown. Therefore, we monitored whether eIF4E-dependent transport could be modulated in response to environmental conditions. Here we report that cadmium treatment, which disperses PML nuclear bodies, leaves eIF4E bodies intact, leading to increased transport of cyclin D1 mRNA and increased cyclin D1 protein levels. Removal of cadmium allows PML to reassociate with eIF4E nuclear bodies, leading to decreased cyclin D1 transport and reduced cyclin D1 protein levels. In contrast, we show that treating cells with interferon increased the levels of PML protein at the PML-eIF4E nuclear body, leading to nuclear retention of cyclin D1 transcripts and reduced cyclin D1 protein levels. Neither interferon nor cadmium treatment altered cyclin D1 levels in PML^-/- cells. Consistently, overexpression of a series of PML and eIF4E mutant proteins established that PML eIF4E interaction is required for the observed effects of cadmium and interferon treatment. The present study provides the first evidence that physiological factors modulate the mRNA transport functions of eIF4E and that this regulation is PML dependent.