E2F-1 Blocks Terminal Differentiation and Causes Proliferation in Transgenic Megakaryocytes

Overview

Journal Mol Cell Biol

Specialty Cell Biology

Date 1996 Feb 1

PMID 8552097

Citations 20

Authors

C T Guy

W Zhou

S Kaufman

M O ROBINSON

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

Fusion oncoproteins and cooperating mutations define disease phenotypes in -rearranged leukemia.

Umeda M, Hiltenbrand R, Michmerhuizen N, Barajas J, Thomas M, Arthur B medRxiv. 2025; .

PMID: 39974131 PMC: 11838931. DOI: 10.1101/2025.01.21.25320683.

Whole genome sequence analysis of platelet traits in the NHLBI Trans-Omics for Precision Medicine (TOPMed) initiative.

Little A, Hu Y, Sun Q, Jain D, Broome J, Chen M Hum Mol Genet. 2021; 31(3):347-361.

PMID: 34553764 PMC: 8825339. DOI: 10.1093/hmg/ddab252.

E2F1 impairs all-trans retinoic acid-induced osteogenic differentiation of osteosarcoma via promoting ubiquitination-mediated degradation of RARα.

Zhang L, Zhou Q, Zhang N, Li W, Ying M, Ding W Cell Cycle. 2014; 13(8):1277-87.

PMID: 24608861 PMC: 4049964. DOI: 10.4161/cc.28190.

C/EBPα regulated microRNA-34a targets E2F3 during granulopoiesis and is down-regulated in AML with CEBPA mutations.

Pulikkan J, Peramangalam P, Dengler V, Ho P, Preudhomme C, Meshinchi S Blood. 2010; 116(25):5638-49.

PMID: 20889924 PMC: 3031410. DOI: 10.1182/blood-2010-04-281600.

Developmental stage-specific interplay of GATA1 and IGF signaling in fetal megakaryopoiesis and leukemogenesis.

Klusmann J, Godinho F, Heitmann K, Maroz A, Koch M, Reinhardt D Genes Dev. 2010; 24(15):1659-72.

PMID: 20679399 PMC: 2912563. DOI: 10.1101/gad.1903410.

References

Nevins J . E2F: a link between the Rb tumor suppressor protein and viral oncoproteins. Science. 1992; 258(5081):424-9. DOI: 10.1126/science.1411535. View

Shan B, Zhu X, Chen P, Durfee T, Yang Y, Sharp D . Molecular cloning of cellular genes encoding retinoblastoma-associated proteins: identification of a gene with properties of the transcription factor E2F. Mol Cell Biol. 1992; 12(12):5620-31. PMC: 360501. DOI: 10.1128/mcb.12.12.5620-5631.1992. View

Gu W, Schneider J, Condorelli G, Kaushal S, Mahdavi V, Nadal-Ginard B . Interaction of myogenic factors and the retinoblastoma protein mediates muscle cell commitment and differentiation. Cell. 1993; 72(3):309-24. DOI: 10.1016/0092-8674(93)90110-c. View

Slansky J, Li Y, Kaelin W, Farnham P . A protein synthesis-dependent increase in E2F1 mRNA correlates with growth regulation of the dihydrofolate reductase promoter. Mol Cell Biol. 1993; 13(3):1610-8. PMC: 359473. DOI: 10.1128/mcb.13.3.1610-1618.1993. View

Girling R, Partridge J, Bandara L, Burden N, Totty N, Hsuan J . A new component of the transcription factor DRTF1/E2F. Nature. 1993; 362(6415):83-7. DOI: 10.1038/362083a0. View

Lam E, Watson R . An E2F-binding site mediates cell-cycle regulated repression of mouse B-myb transcription. EMBO J. 1993; 12(7):2705-13. PMC: 413519. DOI: 10.1002/j.1460-2075.1993.tb05932.x. View

Wiman K . The retinoblastoma gene: role in cell cycle control and cell differentiation. FASEB J. 1993; 7(10):841-5. DOI: 10.1096/fasebj.7.10.8393817. View

Flemington E, Speck S, Kaelin Jr W . E2F-1-mediated transactivation is inhibited by complex formation with the retinoblastoma susceptibility gene product. Proc Natl Acad Sci U S A. 1993; 90(15):6914-8. PMC: 47045. DOI: 10.1073/pnas.90.15.6914. View

Johnson D, Schwarz J, Cress W, Nevins J . Expression of transcription factor E2F1 induces quiescent cells to enter S phase. Nature. 1993; 365(6444):349-52. DOI: 10.1038/365349a0. View

10.

Helin K, Wu C, Fattaey A, Lees J, Dynlacht B, Ngwu C . Heterodimerization of the transcription factors E2F-1 and DP-1 leads to cooperative trans-activation. Genes Dev. 1993; 7(10):1850-61. DOI: 10.1101/gad.7.10.1850. View

11.

Helin K, Harlow E, Fattaey A . Inhibition of E2F-1 transactivation by direct binding of the retinoblastoma protein. Mol Cell Biol. 1993; 13(10):6501-8. PMC: 364709. DOI: 10.1128/mcb.13.10.6501-6508.1993. View

12.

Bandara L, Buck V, Zamanian M, Johnston L, La Thangue N . Functional synergy between DP-1 and E2F-1 in the cell cycle-regulating transcription factor DRTF1/E2F. EMBO J. 1993; 12(11):4317-24. PMC: 413728. DOI: 10.1002/j.1460-2075.1993.tb06116.x. View

13.

Conroy R, Huber H, Goodhart P, Oliff A, Heimbrook D . Cloning and characterization of E2F-2, a novel protein with the biochemical properties of transcription factor E2F. Mol Cell Biol. 1993; 13(12):7802-12. PMC: 364852. DOI: 10.1128/mcb.13.12.7802-7812.1993. View

14.

ODELL Jr T, Jackson C . Polyploidy and maturation of rat megakaryocytes. Blood. 1968; 32(1):102-10. View

15.

Hoffman R . Regulation of megakaryocytopoiesis. Blood. 1989; 74(4):1196-212. View

16.

Ishibashi T, Kimura H, Shikama Y, Uchida T, KARIYONE S, Hirano T . Interleukin-6 is a potent thrombopoietic factor in vivo in mice. Blood. 1989; 74(4):1241-4. View

17.

Mudryj M, Hiebert S, Nevins J . A role for the adenovirus inducible E2F transcription factor in a proliferation dependent signal transduction pathway. EMBO J. 1990; 9(7):2179-84. PMC: 551940. DOI: 10.1002/j.1460-2075.1990.tb07387.x. View

18.

Ravid K, Beeler D, Rabin M, Ruley H, Rosenberg R . Selective targeting of gene products with the megakaryocyte platelet factor 4 promoter. Proc Natl Acad Sci U S A. 1991; 88(4):1521-5. PMC: 51051. DOI: 10.1073/pnas.88.4.1521. View

19.

ROBINSON M, Simon M . Determining transcript number using the polymerase chain reaction: Pgk-2, mP2, and PGK-2 transgene mRNA levels during spermatogenesis. Nucleic Acids Res. 1991; 19(7):1557-62. PMC: 333915. DOI: 10.1093/nar/19.7.1557. View

20.

Szekely L, Jiang W, Bulic-Jakus F, Rosen A, RINGERTZ N, Klein G . Cell type and differentiation dependent heterogeneity in retinoblastoma protein expression in SCID mouse fetuses. Cell Growth Differ. 1992; 3(3):149-56. View