Myeloid differentiation and retinoblastoma phosphorylation changes in HL-60 cells induced by retinoic acid receptor- and retinoid X receptor-selective retinoic acid analogs.
The ability of subtypes of retinoic acid receptors (RARs) and retinoid X receptors (RXRs) singly and in combination to elicit myeloid differentiation, G1/0-specific growth arrest, and retinoblastoma (RB) tumor suppressor protein dephosphorylation was determined in the human myeloblastic leukemia cell line HL-60 using subtype-selective retinoic acid (RA) analogs. RA analogs that selectively bind only to RARs (Am580 and/or TTNPB) or to RXRs (Ro 25-6603, SR11237, and/or SR11234) did not elicit the above-mentioned three cellular responses. In contrast, simultaneous treatment with both an RAR-selective ligand (Am580 or TTNPB) and an RXR-selective ligand (Ro 25-6603, SR11237, or SR11234) induced all three cellular processes. An RAR alpha-selective ligand used with an RXR-selective ligand generated the same responses as did all-trans RA or 9-cis RA, which affect both families of receptors, suggesting an important role for RAR alpha among RAR subtypes in eliciting cellular response. Consistent with this finding, the RAR alpha antagonist, Ro 41-5253, reduced the level of the cellular responses elicited by treatment with an RAR alpha-selective ligand plus RXR-selective ligand. The coupling of the shift of RB to its hypophosphorylated form with G1/0 arrest and differentiation in response to ligands is consistent with a possible role of RB as a downstream target or effector of RAR alpha and RXR in combination.
Department of Pathology, Cornell University, Ithaca, NY 14853, USA.
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Brooks
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Kazmer
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Levin
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Yen
D001565:Benzoates / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D002839:Chromans / Q000494:pharmacology; D003510:Cyclohexanes / Q000494:pharmacology; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D005434:Flow Cytometry; D018922:HL-60 Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008024:Ligands; D009363:Neoplasm Proteins / Q000378:metabolism*; D010421:Pentanoic Acids / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D018168:Receptors, Retinoic Acid / Q000187:drug effects* / Q000502:physiology; D016160:Retinoblastoma Protein / Q000378:metabolism*; D047488:Retinoid X Receptors; D012176:Retinoids / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013764:Tetrahydronaphthalenes / Q000494:pharmacology; D014157:Transcription Factors / Q000187:drug effects* / Q000502:physiology; D014212:Tretinoin / Q000031:analogs & derivatives* / Q000494:pharmacology
D001565:Benzoates; D002839:Chromans; D003510:Cyclohexanes; D005231:Fatty Acids, Unsaturated; D008024:Ligands; D009363:Neoplasm Proteins; D010421:Pentanoic Acids; D018168:Receptors, Retinoic Acid; D016160:Retinoblastoma Protein; D047488:Retinoid X Receptors; D012176:Retinoids; C097598:Ro 25-5802; C097599:Ro 25-6603; D013764:Tetrahydronaphthalenes; D014157:Transcription Factors; C068073:Am 580; C084904:Ro 41-5253; C097595:SR 11234; C087130:SR 11237; D014212:Tretinoin; C038864:4-(2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl)benzoic acid