E2F-1 blocks terminal differentiation and causes proliferation in transgenic megakaryocytes.
The transcription factor E2F-1 plays a central role in the cell cycle through its ability to activate genes involved in cell division. E2F-1 activity is regulated by a number of proteins, including the retinoblastoma susceptibility gene product, cyclin-dependent kinases, and their inhibitors, proteins that have been implicated in the control of certain developmental processes. To investigate a potential role of E2F-1 in differentiation, we assayed the ability of megakaryocytes to form platelets in an in vivo transgenic model. E2F-1 expression in megakaryocytes blocked differentiation during maturation, resulting in severe thrombocytopenia. Ultrastructural analysis of megakaryocytes revealed abnormal development characterized by hyperdemarcation of cytoplasmic membranes and reduced numbers of alpha granules. Administration of megakaryocyte growth and development factor or interleukin 6 could not overcome the differentiation block. Additionally, E2F-1 caused massive megakaryocyte accumulation in both normal and ectopic sites, first evident in E15 embryonic liver. Furthermore, significant apoptosis was observed in transgenic megakaryocytes. These data indicate that E2F-1 can prevent terminal differentiation, probably through its cell cycle-stimulatory activity.
Guy
C T
CT
Amgen, Inc., Thousand Oaks, California 91320, USA.
Zhou
W
W
Kaufman
S
S
Robinson
M O
MO
D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D001792:Blood Platelets / Q000502:physiology*; D002352:Carrier Proteins; D002453:Cell Cycle / Q000235:genetics*; D018797:Cell Cycle Proteins; D002454:Cell Differentiation; D002455:Cell Division; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D006801:Humans; D007150:Immunohistochemistry; D008099:Liver / Q000473:pathology; D008533:Megakaryocytes / Q000473:pathology / Q000502:physiology* / Q000648:ultrastructure; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D010978:Platelet Factor 4 / Q000235:genetics; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D056465:Retinoblastoma-Binding Protein 1; D013154:Spleen / Q000473:pathology; D013921:Thrombocytopenia / Q000235:genetics; D050680:Transcription Factor DP1; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
C533431:Arid4a protein, mouse; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; C493754:E2f1 protein, mouse; D011993:Recombinant Fusion Proteins; D056465:Retinoblastoma-Binding Protein 1; D050680:Transcription Factor DP1; D014157:Transcription Factors; D010978:Platelet Factor 4