The promyelocytic leukemia (PML) protein suppresses cyclin D1 protein production by altering the nuclear cytoplasmic distribution of cyclin D1 mRNA.
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 (elF-4E) co-localize and co-immunopurify. eIF-4E is involved in nucleocytoplasmic transport of specific 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 significant 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 specific mRNAs.
Lai
H K
HK
Department of Physiology & Biophysics, Mount Sinai School of Medicine, New York, NY 10029, USA.
Borden
K L
KL
D016475:3T3 Cells; D000818:Animals; D001692:Biological Transport; D002460:Cell Line; D019938:Cyclin D1 / Q000096:biosynthesis* / Q000235:genetics; D003593:Cytoplasm / Q000737:chemistry*; D039561:Eukaryotic Initiation Factor-4E; D005347:Fibroblasts; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D046911:Macromolecular Substances; D051379:Mice; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics / Q000302:isolation & purification / Q000502:physiology*; D009687:Nuclear Proteins; D015388:Organelles / Q000737:chemistry / Q000502:physiology; D010448:Peptide Initiation Factors / Q000032:analysis / Q000302:isolation & purification; D000071156:Promyelocytic Leukemia Protein; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000378:metabolism*; D012334:RNA, Neoplasm / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000502:physiology; D013347:Subcellular Fractions / Q000737:chemistry; D014157:Transcription Factors / Q000737:chemistry / Q000302:isolation & purification / Q000502:physiology*; D014158:Transcription, Genetic; D014162:Transfection; D025521:Tumor Suppressor Proteins
D039561:Eukaryotic Initiation Factor-4E; D046911:Macromolecular Substances; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D010448:Peptide Initiation Factors; C513293:Pml protein, mouse; D000071156:Promyelocytic Leukemia Protein; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D019938:Cyclin D1; C070576:PML protein, human