Retinoic acid induced HL-60 myeloid differentiation: dependence of early and late events on isomeric structure.
The capability of HL-60 cells to undergo G1/0 specific growth arrest and myeloid differentiation in response to isomers of retinoic acid (RA) having an altered alkyl chain was determined. At a concentration where beta-all trans RA induces myeloid differentiation and G1/0 specific growth arrest, 11,13-dicis and 9,13-dicis isomers failed to induce significant phenotypic differentiation, assayed by the inducible superoxide production characteristic of mature myeloid cells, but could induce moderate G1/0 specific growth arrest. The 9-cis and 11-cis isomers induced both phenotypic differentiation and G1/0 specific growth arrest. The occurrence of G1/0 specific growth arrest without phenotypic differentiation indicates that the induced cellular programs leading to phenotypic differentiation and G1/0 specific growth arrest are not tightly coupled. Within the 48-h period usually required by beta-all trans RA to induce onset of phenotypic differentiation and G1/0 specific growth arrest, all isomers could complete early events in the cellular programs leading to G1/0 specific growth arrest and phenotypic differentiation, but the dicis isomers could not complete late events in the phenotypic differentiation program. The capability of dicis isomers to drive late events in the G1/0 specific growth arrest program was also compromised. Characteristic early and late changes in Ca2+ binding cytosolic proteins induced by RA and its isomers were consistent with their early and late capabilities. Failure of the dicis isomers to induce differentiation was thus due to a failure in late events associated with aberrations in cytosolic, Ca2+ binding proteins. The results suggest a model in which RA presents two signals to induce HL-60 terminal differentiation.
Yen
A
A
Powers
V
V
Fishbaugh
J
J
D002135:Calcium-Binding Proteins / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D002467:Cell Nucleus / Q000648:ultrastructure; D003600:Cytosol / Q000378:metabolism; D006801:Humans; D007536:Isomerism; D007700:Kinetics; D015470:Leukemia, Myeloid, Acute / Q000473:pathology*; D008970:Molecular Weight; D009363:Neoplasm Proteins / Q000378:metabolism; D013329:Structure-Activity Relationship; D013997:Time Factors; D014212:Tretinoin / Q000494:pharmacology*
D002135:Calcium-Binding Proteins; D009363:Neoplasm Proteins; D014212:Tretinoin