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
In normal mammalian cells the promyelocytic leukemia protein (PML) is primarily localized in multiprotein nuclear complexes called PML nuclear bodies. However, both PML and PML nuclear bodies are disrupted in acute promyelocytic leukemia (APL). The treatment of APL patients with all-trans retinoic acid (ATRA) results in clinical remission associated with blast cell differentiation and reformation of the PML nuclear bodies. These observations imply that the structural integrity of the PML nuclear body is critically important for normal cellular functions. Indeed, PML protein is a negative growth regulator capable of causing growth arrest in the G 1 phase of the cell cycle, transformation suppression, senescence and apoptosis. These PML-mediated, physiological effects can be readily demonstrated. However, a discrete biochemical and molecular model of PML function has yet to be defined. Upon first assessment of the current PML literature there appears to be a seemingly endless list of potential PML partner proteins implicating PML in a variety of regulatory mechanisms at every level of gene expression. The purpose of this review is to simplify this confusing field of research by using strict criteria to deduce which models of PML body function are well supported.
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