A novel mechanism for BCR-ABL action: stimulated secretion of CCN3 is involved in growth and differentiation regulation.

2.50
Hdl Handle:
http://hdl.handle.net/10541/72757
Title:
A novel mechanism for BCR-ABL action: stimulated secretion of CCN3 is involved in growth and differentiation regulation.
Authors:
McCallum, Lynne; Price, Susan; Planque, Nathalie; Perbal, Bernard; Pierce, Andrew; Whetton, Anthony D; Irvine, Alexandra E
Abstract:
Chronic myeloid leukemia (CML) is characterized by the presence of the constitutively active BCR-ABL protein tyrosine kinase. Using a multipotent hemopoietic cell line, FDCP-Mix, expressing BCR-ABL tyrosine kinase, we investigated the initial effects of this kinase in primitive hematopoietic stem cells. We identified down-regulation of a novel gene, CCN3, as a direct consequence of BCR-ABL kinase activity. CCN3 has been reported to function as a tumor suppressor gene in solid tumors. Northern and Western blotting plus immunocytochemical analysis confirmed CCN3 expression is decreased and is tyrosine-phosphorylated in BCR-ABL kinase active FDCP-Mix cells. Decreased cellular CCN3 correlated with increased CCN3 secretion in BCR-ABL kinase active cells. In vitro treatment of human CML cell lines with imatinib or siRNA directed against BCR-ABL significantly reduced BCR-ABL while increasing CCN3 expression. Cells from patients responding to imatinib showed a similar decrease in BCR-ABL and increase in CCN3. CML CD34+ cells treated with imatinib in vitro demonstrated increased CCN3 protein. Transfecting CCN3 into BCR-ABL+ cells inhibited proliferation and decreased clonogenic potential. CCN3 plays an important role in internal and external cell-signaling pathways. Thus, BCR-ABL can regulate protein levels by governing secretion, a novel mechanism for this tyrosine kinase.
Affiliation:
Department of Haematology, Centre for Cancer Research and Cell Biology, Queen's University Belfast, University Floor, Tower Block, Belfast City Hospital, Lisburn Road, Belfast BT9 7AB, United Kingdom.
Citation:
A novel mechanism for BCR-ABL action: stimulated secretion of CCN3 is involved in growth and differentiation regulation. 2006, 108 (5):1716-23 Blood
Journal:
Blood
Issue Date:
1-Sep-2006
URI:
http://hdl.handle.net/10541/72757
DOI:
10.1182/blood-2006-04-016113
PubMed ID:
16670264
Type:
Article
Language:
en
ISSN:
0006-4971
Appears in Collections:
All Paterson Institute for Cancer Research

Full metadata record

DC FieldValue Language
dc.contributor.authorMcCallum, Lynne-
dc.contributor.authorPrice, Susan-
dc.contributor.authorPlanque, Nathalie-
dc.contributor.authorPerbal, Bernard-
dc.contributor.authorPierce, Andrew-
dc.contributor.authorWhetton, Anthony D-
dc.contributor.authorIrvine, Alexandra E-
dc.date.accessioned2009-07-07T11:50:48Z-
dc.date.available2009-07-07T11:50:48Z-
dc.date.issued2006-09-01-
dc.identifier.citationA novel mechanism for BCR-ABL action: stimulated secretion of CCN3 is involved in growth and differentiation regulation. 2006, 108 (5):1716-23 Blooden
dc.identifier.issn0006-4971-
dc.identifier.pmid16670264-
dc.identifier.doi10.1182/blood-2006-04-016113-
dc.identifier.urihttp://hdl.handle.net/10541/72757-
dc.description.abstractChronic myeloid leukemia (CML) is characterized by the presence of the constitutively active BCR-ABL protein tyrosine kinase. Using a multipotent hemopoietic cell line, FDCP-Mix, expressing BCR-ABL tyrosine kinase, we investigated the initial effects of this kinase in primitive hematopoietic stem cells. We identified down-regulation of a novel gene, CCN3, as a direct consequence of BCR-ABL kinase activity. CCN3 has been reported to function as a tumor suppressor gene in solid tumors. Northern and Western blotting plus immunocytochemical analysis confirmed CCN3 expression is decreased and is tyrosine-phosphorylated in BCR-ABL kinase active FDCP-Mix cells. Decreased cellular CCN3 correlated with increased CCN3 secretion in BCR-ABL kinase active cells. In vitro treatment of human CML cell lines with imatinib or siRNA directed against BCR-ABL significantly reduced BCR-ABL while increasing CCN3 expression. Cells from patients responding to imatinib showed a similar decrease in BCR-ABL and increase in CCN3. CML CD34+ cells treated with imatinib in vitro demonstrated increased CCN3 protein. Transfecting CCN3 into BCR-ABL+ cells inhibited proliferation and decreased clonogenic potential. CCN3 plays an important role in internal and external cell-signaling pathways. Thus, BCR-ABL can regulate protein levels by governing secretion, a novel mechanism for this tyrosine kinase.en
dc.language.isoenen
dc.subjectLeukaemiaen
dc.subject.meshBase Sequence-
dc.subject.meshBlotting, Northern-
dc.subject.meshCell Differentiation-
dc.subject.meshCell Division-
dc.subject.meshConnective Tissue Growth Factor-
dc.subject.meshDNA Primers-
dc.subject.meshFusion Proteins, bcr-abl-
dc.subject.meshGene Expression Regulation, Neoplastic-
dc.subject.meshHumans-
dc.subject.meshImmediate-Early Proteins-
dc.subject.meshIntercellular Signaling Peptides and Proteins-
dc.subject.meshK562 Cells-
dc.subject.meshLeukemia, Myelogenous, Chronic, BCR-ABL Positive-
dc.subject.meshNephroblastoma Overexpressed Protein-
dc.subject.meshOligonucleotide Array Sequence Analysis-
dc.subject.meshRNA, Small Interfering-
dc.subject.meshReference Values-
dc.subject.meshTransfection-
dc.titleA novel mechanism for BCR-ABL action: stimulated secretion of CCN3 is involved in growth and differentiation regulation.en
dc.typeArticleen
dc.contributor.departmentDepartment of Haematology, Centre for Cancer Research and Cell Biology, Queen's University Belfast, University Floor, Tower Block, Belfast City Hospital, Lisburn Road, Belfast BT9 7AB, United Kingdom.en
dc.identifier.journalBlooden

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