STIMULATING CELL-PROLIFERATION THROUGH THE PHARMACOLOGICAL ACTIVATIONOF C-KIT

Citation
Lq. Jin et al., STIMULATING CELL-PROLIFERATION THROUGH THE PHARMACOLOGICAL ACTIVATIONOF C-KIT, Blood, 91(3), 1998, pp. 890-897
Citations number
44
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Hematology
Journal title
BloodACNP
ISSN journal
0006-4971
Volume
91
Issue
3
Year of publication
1998
Pages
890 - 897
Database
ISI
SICI code
0006-4971(1998)91:3<890:SCTTPA>2.0.ZU;2-C
Abstract
Previous studies have shown that expression of a membrane targeted chi meric protein containing the erythropoietin receptor (EpoR) cytoplasmi c domain fused to the FK506-binding peptide FKBP12 allowed Ba/F3 cells to be rescued from interleukin-3 (IL-3) deprivation using a dimeric f orm of FK506, called FK1012. In this report, a similar approach is app lied to the c-kit receptor. Expression of a membrane targeted fusion p rotein containing the c-kit receptor linked to one or more copies of F KBP12 allowed Ba/F3 cells to be switched from IL-3 dependence to FK101 2-dependence. Similar results were obtained using an alternative dimer izer of FKBP12 domains called AP1510. Pharmacologic dimerization of ch imeric proteins containing only a single FKBP12 domain confirmed that receptor dimerization is sufficient for proliferative signaling. Inter estingly, while the proliferative effects of both FK1012 and AP1510 we re reversible, FK1012-driven proliferation persisted for several days after drug withdrawal. Furthermore, much higher concentrations of FK50 6 were required to inhibit FK1012-mediated proliferation than were req uired to inhibit AP1510-mediated proliferation. The persistence of FK1 012's effect appeared to be specific to clones expressing c-kit-contai ning fusion proteins. These results suggest that pharmacologically-res ponsive fusion proteins containing c-kit may be useful for specificall y and reversibly expanding genetically modified hematopoietic cell pop ulations, (C) 1998 by The American Society of Hematology.