title: BCR-ABL and interleukin 3 promote haematopoietic cell proliferation and survival through modulation of cyclin D2 and p27Kip1 expression.
abstract: Although it is evident that BCR-ABL can rescue cytokine-deprived hematopoietic progenitor cells from cell cycle arrest and apoptosis, the exact mechanism of action of BCR/ABL and interleukin (IL)-3 to promote proliferation and survival has not been established. Using the pro-B cell line BaF3 and a BaF3 cell line stably overexpressing BCR-ABL (BaF3-p210), we investigated the proliferative signals derived from BCR-ABL and IL-3. The results indicate that both IL-3 and BCR-ABL target the expression of cyclin Ds and down-regulation of p27(Kip1) to mediate pRB-related pocket protein phosphorylation, E2F activation, and thus S phase progression. These findings were further confirmed in a BaF3 cell line (TonB.210) where the BCR-ABL expression is inducible by doxycyclin and by using the drug STI571 to inactivate BCR-ABL activity in BaF3-p210. To establish the functional significance of cyclin D2 and p27(Kip1) expression in response to IL-3 and BCR-ABL expression, we studied the effects of ectopic expression of cyclin D2 and p27(Kip1) on cell proliferation and survival. Our results demonstrate that both cyclin D2 and p27(Kip1) have a role in BaF3 cell proliferation and survival, as ectopic expression of cyclin D2 is sufficient to abolish the cell cycle arrest and apoptosis induced by IL-3 withdrawal or by BCR-ABL inactivation, while overexpression of p27(Kip1) can cause cell cycle arrest and apoptosis in the BaF3 cells. Furthermore, our data also suggest that cyclin D2 functions upstream of p27(Kip1), cyclin E, and cyclin D3, and therefore, plays an essential part in integrating the signals from IL-3 and BCR-ABL with the pRB/E2F pathway.
authors.affiliation: Ludwig Institute for Cancer Research and Section of Virology and Cell Biology, Imperial College School of Medicine at St Mary's, Norfolk Place, London W2 1PG, United Kingdom.
authors.forename: Y
authors.initials: Y
authors.lastname: Parada
authors.forename: L
authors.initials: L
authors.lastname: Banerji
authors.forename: J
authors.initials: J
authors.lastname: Glassford
authors.forename: N C
authors.initials: NC
authors.lastname: Lea
authors.forename: M
authors.initials: M
authors.lastname: Collado
authors.forename: C
authors.initials: C
authors.lastname: Rivas
authors.forename: J L
authors.initials: JL
authors.lastname: Lewis
authors.forename: M Y
authors.initials: MY
authors.lastname: Gordon
authors.forename: N S
authors.initials: NS
authors.lastname: Thomas
authors.forename: E W
authors.initials: EW
authors.lastname: Lam
mesh_terms: D000818:Animals; D017209:Apoptosis; D001549:Benzamides; D018797:Cell Cycle Proteins / Q000096:biosynthesis* / Q000235:genetics; D002455:Cell Division; D002460:Cell Line; D002470:Cell Survival; D056742:Cyclin D2; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016213:Cyclins / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D016193:G1 Phase; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000187:drug effects; D000068877:Imatinib Mesylate; D007377:Interleukin-3 / Q000494:pharmacology / Q000502:physiology*; D010879:Piperazines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D016160:Retinoblastoma Protein / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic; D025521:Tumor Suppressor Proteins
chemical_list: D001549:Benzamides; C080336:CCND2 protein, human; D018797:Cell Cycle Proteins; D056742:Cyclin D2; D016213:Cyclins; D004791:Enzyme Inhibitors; D007377:Interleukin-3; D010879:Piperazines; D011743:Pyrimidines; D012333:RNA, Messenger; D016160:Retinoblastoma Protein; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl