The promyelocytic leukemia (PML) protein suppresses cyclin D1 protein production by altering the nuclear cytoplasmic distribution of cyclin D1 mRNA

Abstract

The majority of the promyelocytic leukemia (PML) protein is present in nuclear bodies which are altered in several pathogenic conditions including acute promyelocytic leukemia. PML nuclear bodies are found in nearly all cells yet their function remains unknown. Here, we demonstrate that PML and the eukaryotic initiation factor 4E (eIF-4E) co-localize and co-immunopurify. eIF-4E is involved in nucleocytoplasmic transport of speci®c mRNAs including cyclin D1. eIF-4E overexpression leads to increased cyclin D1 protein levels; whereas, overexpression of PML leads to decreased cyclin D1 levels. Neither PML nor eIF-4E cause signi®cant changes in cyclin D1 mRNA levels. The association with eIF-4E led us to investigate if PML could alter mRNA distribution as a possible post-transcriptional mechanism for suppressing cyclin D1 production. We show that overexpression of PML results in nuclear retention of cyclin D1 mRNA and that intact PML nuclear bodies are required. Addition of eIF-4E overcomes PML induced retention and alters the morphology of PML bodies suggesting a mechanism by which eIF-4E can modulate PML function. These results raise the possibility that PML nuclear bodies may participate in the regulation of nucleocytoplasmic transport of speci®c mRNAs.

The ERK1/2 mitogen-activated protein kinase pathway as a master regulator of the G1- to S-phase transition

“…An important fraction of cellular eIF4E is found within the nucleus, where it associates with nuclear bodies (reviewed in Strudwick and Borden, 2002). In this compartment, eIF4E functions to promote the nucleo-cytoplasmic export of a subset of growth-associated mRNAs including cyclin D1 (Rousseau et al, 1996;Lai and Borden, 2000;Topisirovic et al, 2002) by a mechanism involving an 100-nucleotide sequence in the 3 0 UTR of cyclin D1 mRNA (Culjkovic et al, 2005). Mutation of Ser 209 or treatment with the synthetic inhibitor of Mnk1/Mnk2 CGP57380 markedly reduced the nuclear export of cyclin D1 mRNA by eIF4E, demonstrating the importance of phosphorylation in this process (Topisirovic et al, 2004).…”

Acute promyelocytic leukemia: PML/RARα and the leukemic stem cell

“…The eIF-4E is a cap binding protein that regulates the nucleocytoplasmic transport of a subset of transcripts including Cyclin D1. 72 Overexpression of eIF-4E increases the protein level of Cyclin D1 by augmenting its cytoplasmic mRNA, 73 and moreover overexpression of eIF-4E promotes growth and oncogenic transformation. 74 PML and eIF-4E colocalize in the PML-NBs and directly interact through the PML RING domain.…”

Target of Rapamycin (TOR)-signaling and RAIP Motifs Play Distinct Roles in the Mammalian TOR-dependent Phosphorylation of Initiation Factor 4E-binding Protein 1

“…For example, overexpression of eIF4E can transform cells (4,5), and many human tumor cells express high levels of this protein (6). Nuclear eIF4E seems to be important in the export of certain mRNAs to the cytoplasm such as that for cyclin D1 (7), which is important in cell cycle progression.The transforming abilities of eIF4E may be linked to this effect (8,9).The availability of eIF4E for binding to eIF4G is regulated by its interaction with heat-stable proteins termed eIF4E-binding proteins (4E-BPs). 4E-BP1 is by far the best understood of these.…”