Bcr-Abl protein tyrosine kinase activity induces a loss of p53 protein that mediates a delay in myeloid differentiation.

2.50
Hdl Handle:
http://hdl.handle.net/10541/90042
Title:
Bcr-Abl protein tyrosine kinase activity induces a loss of p53 protein that mediates a delay in myeloid differentiation.
Authors:
Pierce, Andrew; Spooncer, Elaine; Wooley, Sarah; Dive, Caroline ( 0000-0002-1726-8850 ) ; Francis, Julia M; Miyan, Jaleel; Owen-Lynch, P Jane; Dexter, T Michael; Whetton, Anthony D
Abstract:
Chronic myeloid leukaemia is a haemopoietic stem cell disorder, the hallmark of which is the expression of the Bcr-Abl Protein Tyrosine Kinase (PTK). We have previously reported that activation of a temperature sensitive Bcr-Abl PTK in the multipotent haemopoietic cell line FDCP-Mix for short periods resulted in subtle changes including, a transient suppression of apoptosis and no inhibition of differentiation. In contrast, activation of the Bcr-Abl PTK for 12 weeks results in cells that display a delay in differentiation at the early granulocyte stage. Flow cytometric analysis also indicates that the expression of cell surface differentiation markers and nuclear morphology are uncoupled. Furthermore, a significant number of the mature neutrophils display abnormal morphological features. Prolonged exposure to Bcr-Abl PTK results in interleukin-3 independent growth and decreased p53 protein levels. FDCP-Mix cells expressing a dominant negative p53 and p53null FDCP-Mix cells demonstrate that the reduction in p53 is causally related to the delay in development. Returning the cells to the restrictive temperature restores the p53 protein levels, the growth factor dependence and largely relieves the effects on development. We conclude that prolonged Bcr-Abl PTK activity within multipotent cells results in a reduction of p53 that drives a delayed and abnormal differentiation.
Affiliation:
Leukaemia Research Fund Cellular Development Unit, UMIST, Manchester, UK.
Citation:
Bcr-Abl protein tyrosine kinase activity induces a loss of p53 protein that mediates a delay in myeloid differentiation. 2000, 19 (48):5487-97 Oncogene
Journal:
Oncogene
Issue Date:
16-Nov-2000
URI:
http://hdl.handle.net/10541/90042
DOI:
10.1038/sj.onc.1203940
PubMed ID:
11114726
Type:
Article
Language:
en
ISSN:
0950-9232
Appears in Collections:
All Paterson Institute for Cancer Research

Full metadata record

DC FieldValue Language
dc.contributor.authorPierce, Andrewen
dc.contributor.authorSpooncer, Elaineen
dc.contributor.authorWooley, Sarahen
dc.contributor.authorDive, Carolineen
dc.contributor.authorFrancis, Julia Men
dc.contributor.authorMiyan, Jaleelen
dc.contributor.authorOwen-Lynch, P Janeen
dc.contributor.authorDexter, T Michaelen
dc.contributor.authorWhetton, Anthony Den
dc.date.accessioned2010-01-19T17:12:27Z-
dc.date.available2010-01-19T17:12:27Z-
dc.date.issued2000-11-16-
dc.identifier.citationBcr-Abl protein tyrosine kinase activity induces a loss of p53 protein that mediates a delay in myeloid differentiation. 2000, 19 (48):5487-97 Oncogeneen
dc.identifier.issn0950-9232-
dc.identifier.pmid11114726-
dc.identifier.doi10.1038/sj.onc.1203940-
dc.identifier.urihttp://hdl.handle.net/10541/90042-
dc.description.abstractChronic myeloid leukaemia is a haemopoietic stem cell disorder, the hallmark of which is the expression of the Bcr-Abl Protein Tyrosine Kinase (PTK). We have previously reported that activation of a temperature sensitive Bcr-Abl PTK in the multipotent haemopoietic cell line FDCP-Mix for short periods resulted in subtle changes including, a transient suppression of apoptosis and no inhibition of differentiation. In contrast, activation of the Bcr-Abl PTK for 12 weeks results in cells that display a delay in differentiation at the early granulocyte stage. Flow cytometric analysis also indicates that the expression of cell surface differentiation markers and nuclear morphology are uncoupled. Furthermore, a significant number of the mature neutrophils display abnormal morphological features. Prolonged exposure to Bcr-Abl PTK results in interleukin-3 independent growth and decreased p53 protein levels. FDCP-Mix cells expressing a dominant negative p53 and p53null FDCP-Mix cells demonstrate that the reduction in p53 is causally related to the delay in development. Returning the cells to the restrictive temperature restores the p53 protein levels, the growth factor dependence and largely relieves the effects on development. We conclude that prolonged Bcr-Abl PTK activity within multipotent cells results in a reduction of p53 that drives a delayed and abnormal differentiation.en
dc.language.isoenen
dc.subjectLeukaemiaen
dc.subjectCultured Tumour Cellsen
dc.subjectTumour Suppressor Protein p53en
dc.subject.meshAnimals-
dc.subject.meshCell Differentiation-
dc.subject.meshFusion Proteins, bcr-abl-
dc.subject.meshGene Silencing-
dc.subject.meshGenes, p53-
dc.subject.meshHumans-
dc.subject.meshInterleukin-3-
dc.subject.meshLeukemia, Myelogenous, Chronic, BCR-ABL Positive-
dc.subject.meshMice-
dc.subject.meshMyeloid Cells-
dc.subject.meshProtein-Tyrosine Kinases-
dc.subject.meshTemperature-
dc.subject.meshTumor Cells, Cultured-
dc.subject.meshTumor Suppressor Protein p53-
dc.titleBcr-Abl protein tyrosine kinase activity induces a loss of p53 protein that mediates a delay in myeloid differentiation.en
dc.typeArticleen
dc.contributor.departmentLeukaemia Research Fund Cellular Development Unit, UMIST, Manchester, UK.en
dc.identifier.journalOncogeneen

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