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Deregulated E2F-1 blocks terminal differentiation and loss of leukemogenicity of M1 myeloblastic leukemia cells without abrogating induction of p15(INK4B) and p16(INK4A).
- Source :
-
Blood [Blood] 2000 Jul 15; Vol. 96 (2), pp. 475-82. - Publication Year :
- 2000
-
Abstract
- The transcription factor E2F-1 has been postulated to play a crucial role in the control of cell cycle progression because of its ability to be bound and regulated by the retinoblastoma gene product (pRb). Exogenous expression of E2F-1, under growth restrictive conditions, was shown to result in p53-dependent programmed cell death. The consequences of deregulated expression of E2F-1 on terminal differentiation of hematopoietic cells in the absence of E2F-1-mediated apoptosis, as well as mechanistic insights into how deregulated E2F-1 may affect terminal differentiation, have not been established. The autonomously proliferating M1 myeloblastic leukemia cell line, which is null for p53 expression and can be induced by interleukin-6 (IL-6) to undergo terminal macrophage differentiation with concomitant loss of leukemogenicity, provides a particularly attractive model system to address these issues. Deregulated and continued expression of E2F-1 blocked the IL-6-induced terminal differentiation program at an early blast stage, giving rise to immature cells, which continued to proliferate without undergoing apoptosis and retained their leukemogenic phenotype. Although E2F-1 blocked IL-6-mediated terminal differentiation and its associated growth arrest, it did not prevent the rapid induction of both p15(INK4B) and p16(INK4A), inhibition of cdk4 kinase activity, and subsequent hypophosphorylation of pRb. The results obtained imply that genetic alterations that both impair p53 function and deregulate E2F-1 expression may render hematopoietic cells refractory to the induction of differentiation and are, thereby, likely to play a major role in the progression of leukemias. (Blood. 2000;96:475-482)
- Subjects :
- Animals
Apoptosis drug effects
Cell Division drug effects
Cyclin-Dependent Kinase Inhibitor p15
Cyclin-Dependent Kinase Inhibitor p16
E2F Transcription Factors
E2F1 Transcription Factor
Interleukin-6 pharmacology
Leukemia, Myeloid, Acute metabolism
Mice
Mice, Nude
Neoplasm Transplantation
Recombinant Proteins pharmacology
Retinoblastoma-Binding Protein 1
Transcription Factor DP1
Transcription Factors genetics
Tumor Cells, Cultured
Carrier Proteins biosynthesis
Cell Cycle Proteins
Cell Differentiation drug effects
DNA-Binding Proteins
Gene Expression Regulation
Leukemia, Myeloid, Acute pathology
Transcription Factors pharmacology
Tumor Suppressor Proteins
Subjects
Details
- Language :
- English
- ISSN :
- 0006-4971
- Volume :
- 96
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Blood
- Publication Type :
- Academic Journal
- Accession number :
- 10887108